EP2370471A1 - Konjugate aus neurotensin oder neurotensin-analoga und ihre verwendung - Google Patents

Konjugate aus neurotensin oder neurotensin-analoga und ihre verwendung

Info

Publication number
EP2370471A1
EP2370471A1 EP09829934A EP09829934A EP2370471A1 EP 2370471 A1 EP2370471 A1 EP 2370471A1 EP 09829934 A EP09829934 A EP 09829934A EP 09829934 A EP09829934 A EP 09829934A EP 2370471 A1 EP2370471 A1 EP 2370471A1
Authority
EP
European Patent Office
Prior art keywords
pain
compound
angiopep
neurotensin
seq
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP09829934A
Other languages
English (en)
French (fr)
Other versions
EP2370471A4 (de
EP2370471B1 (de
Inventor
Jean-Paul Castaigne
Michel Demeule
Christian Che
Carine Thiot
Catherine Gagnon
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Angiochem Inc
Original Assignee
Angiochem Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Angiochem Inc filed Critical Angiochem Inc
Publication of EP2370471A1 publication Critical patent/EP2370471A1/de
Publication of EP2370471A4 publication Critical patent/EP2370471A4/de
Application granted granted Critical
Publication of EP2370471B1 publication Critical patent/EP2370471B1/de
Not-in-force legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • C07K7/083—Neurotensin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/81—Protease inhibitors
    • C07K14/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
    • C07K14/811—Serine protease (E.C. 3.4.21) inhibitors
    • C07K14/8114—Kunitz type inhibitors
    • C07K14/8117—Bovine/basic pancreatic trypsin inhibitor (BPTI, aprotinin)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/03—Fusion polypeptide containing a localisation/targetting motif containing a transmembrane segment

Definitions

  • the invention relates to compounds including neurotensin, a neurotensin analog, or a neurotensin receptor agonist bound to a peptide vector and uses thereof.
  • Neurotensin is 13 amino acid peptide possessing numerous biological activities. Injections of neurotensin in the central nervous system produce, among other effects, antipsychotic and hypothermic effects. Intravenous delivery of neurotensin, however, does not result in these effects, as the blood-brain barrier (BBB) effectively prevents peripheral neurotensin from reaching the receptors in the central nervous system (CNS) receptors.
  • BBB blood-brain barrier
  • body temperature provides one of the best forms of neuroprotection against brain damage resulting from injury (e.g., in subjects who have suffered from a nerve, brain, or spinal cord injury, or stroke).
  • methods for reducing body temperature have been inadequate.
  • Physical means for reducing body temperature include the use of external methods (e.g., cooling blankets, cooling helmet, ice packs, and ice baths) as well as the use of internal methods (e.g., cooling probes, infusion of cold fluid). These techniques can be complex and expensive, and can lead to delays in the onset of hypothermia. Sustained maintenance of hypothermia may also be difficult using these methods. Finally, these methods can cause severe shivering, necessitating the need for co- medications such as paralytic agents or sedatives. Given the number of strokes
  • ATTORNEY DOCKET NO. V82774WO diseases The reason for this imbalance is, in part, that more than 98% of all potential CNS drugs do not cross the BBB. In addition, more than 99% of worldwide CNS drug development is devoted solely to CNS drug discovery, and less than 1% is directed to CNS drug delivery. This may explain the lack of therapeutic options available for major neurological diseases.
  • the brain is shielded against potentially toxic substances by the presence of two barrier systems: the BBB and the blood-cerebrospinal fluid barrier (BCSFB).
  • BBB is considered to be the major route for the uptake of serum ligands since its surface area is approximately 5000-fold greater than that of BCSFB.
  • the brain endothelium, which constitutes the BBB, represents the major obstacle for the use of potential drugs against many disorders of the CNS. As a general rule, only small lipophilic molecules may pass across the BBB, i.e., from circulating systemic blood to brain. Many drugs that have a larger size or higher hydrophobicity show high efficacy in CNS targets but are not efficacious in animals as these drugs cannot effectively cross the BBB.
  • Brain capillary endothelial cells are closely sealed by tight junctions, possess few fenestrae and few endocytic vesicles as compared to capillaries of other organs. BCECs are surrounded by extracellular matrix, astrocytes, pericytes, and microglial cells. The close association of endothelial cells with the astrocyte foot processes and the basement membrane of capillaries are important for the development and maintenance of the BBB properties that permit tight control of blood-brain exchange.
  • the peptide neurotensin has a number of clinical uses, including the ability to reduce body temperature. Many of these applications, however, require that the peptide cross the blood-brain barrier (BBB).
  • BBB blood-brain barrier
  • Neurotensin by itself, is unable to cross the BBB.
  • a polypeptide therapeutic selected from the group consisting of neurotensin, a neurotensin analog (e.g., pELYENKPRRPYIL-OH, PATENT
  • ATTORNEY DOCKET NO. V82774W0 where "pE” represents L-pyroglutamic acid, human neurotensin(8-13) (NT(8-13)), Ac-Lys-[D-Tyr ⁇ ]NT(8-13), Ac-Lys-NT(8-13), pE-Lys-NT(8-13),), or a neurotensin receptor agonist and (b) a peptide vector capable of transporting the peptide therapeutic across the blood-brain barrier (BBB) or into particular cell types.
  • BBB blood-brain barrier
  • These compounds are useful in treating any disorder where increased neurotensin activity is desired, particularly where transport of the polypeptide therapeutic across the BBB or into a particular cell type is desired.
  • the compound includes neurotensin or a neurotensin fragment which may be used to reduce body temperature (e.g., in a patient who is in need of neuroprotection and/or has had a stroke, heart attack, nerve injury (e.g., spinal chord, head, or brain injury, such as a traumatic brain injury, or is having major surgery such as cardiac surgery or open heart surgery), to treat a patient suffering from a psychiatric disorder (e.g., schizophrenia, obsessive compulsive disorder, or Tourette's syndrome), or to treat a patient suffering from a metabolic disorder such as diabetes and obesity.
  • a psychiatric disorder e.g., schizophrenia, obsessive compulsive disorder, or Tourette's syndrome
  • the compound may be able to either increase or reduce blood pressure in a patient.
  • the compound may be capable of inducing hypothermia, upon either a single or upon an infusion for a period of at least 1, 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, 24, 30, 36, or 48 hours following initial administration.
  • the peptide vector is capable of transporting the polypeptide therapeutic either across the blood-brain barrier (BBB) or into a particular cell type (e.g., liver, lung, kidney, spleen, and muscle). Because the conjugates are targeted across the BBB or to particular cell types, therapeutic efficacy can be achieved using lower doses or less frequent dosing as compared to the unconjugated peptide therapeutic, thus reducing the severity of or incidence of side effects and/or increasing efficacy.
  • the compound may also exhibit increased stability, improved pharmacokinetics, or reduced degradation in vivo, as compared to the unconjugated peptide therapeutic.
  • the invention features a compound having the formula:
  • A-X-B where A is a peptide vector capable of being transported across the blood-brain barrier (BBB) or into a particular cell type (e.g., liver, lung, kidney, spleen, and muscle), X is a linker, and B is a peptide therapeutic selected from the group consisting of neurotensin, a neurotensin analog (e.g., pELYENKPRRPYIL-OH, PATENT
  • B includes or is a polypeptide substantially identical to human neurotensin or to a human neurotensin fragment (e.g., neurotensin(8-13) and neurotensin(9-13)).
  • the glutamate at position 1 of neurotensin is substituted with pyroglutamic acid.
  • the neurotensin analog is substantially identical to human neurotensin.
  • B acts as an agonist to any of the neurotensin receptors (neurotensin receptor type 1 (NTRl), neurotensin receptor type 2 (NTR2), neurotensin receptor 3 (NTR3)).
  • the neurotensin receptor agonist is selective (e.g., binds and/or activates to a degree at least 2, 5, 10, 50, 100, 500, 1000, 5000, 10,000, 50,000, or 100,000 greater) for one of NTRl, NTR2, or NTR3 over at least one of the other receptors.
  • the compound has the structure: pELYENKPRRPYIL — OH
  • AN2Cys-NH2 5 where the -(CH 2 ) 4 NH- moiety attached to the lysine of the pELYENKPRRPYIL sequence represents the side chain of that lysine, and the -CH 2 S- moiety attached to the C-terminal cysteine of the AN2Cys sequence represents the side chain of that cysteine, and AN2 represents the sequence of Angiopep-2 (SEQ ID NO:97).
  • the invention features methods of making the compound A- X-B.
  • the method includes conjugating the peptide vector (A) to a linker (X), and conjugating the peptide vector-linker (A-X) to a peptide therapeutic (B), thereby forming the compound A-X-B.
  • the method includes conjugating the peptide therapeutic (B) to a linker (X), and conjugating the PATENT
  • the method includes conjugating the peptide vector (A) to a peptide therapeutic (B), where either A or B optionally include a linker (X), to form the compound A-X-B.
  • the invention features a nucleic acid molecule that encodes the compound A-X-B, where the compound is a polypeptide.
  • the nucleic acid molecule may be operably linked to a promoter and may be part of a nucleic acid vector.
  • the vector may be in a cell, such as a prokaryotic cell (e.g., bacterial cell) or eukaryotic cell (e.g., yeast or mammalian cell, such as a human cell).
  • a prokaryotic cell e.g., bacterial cell
  • eukaryotic cell e.g., yeast or mammalian cell, such as a human cell.
  • the invention features methods of making a compound of the formula A-X-B, where A-X-B is a polypeptide.
  • the method includes expressing a nucleic acid vector of the previous aspect in a cell to produce the polypeptide; and purifying the polypeptide.
  • the invention features a method of reducing a subject's body temperature.
  • the method includes administering a compound of the first aspect in an amount sufficient to reduce the body temperature of the subject.
  • the subject may be suffering from, or may have recently suffered from, a stroke, cerebral ischemia, cardiac ischemia, or a nerve injury such as a brain injury (e.g., a traumatic brain injury) or a spinal chord injury or may be in need of neuroprotection.
  • the subject may be suffering from malignant hyperthermia or may be undergoing or about to undergo surgery (e.g., major surgery such as cardiac surgery).
  • the invention features a method of reducing pain or inducing analgesia by administering in a compound of the first aspect to a subject in need thereof.
  • the subject may be suffering from an acute pain (e.g., selected from the group consisting of mechanical pain, heat pain, cold pain, ischemic pain, and chemical-induced pain).
  • the subject is suffering from peripheral or central neuropathic pain, inflammatory pain, migraine-related pain, headache-related pain, irritable bowel syndrome-related pain, fibromyalgia-related pain, arthritic pain, skeletal pain, joint pain, gastrointestinal pain, muscle pain, angina pain, facial pain, pelvic pain, claudication, postoperative pain, post traumatic pain, tension-type headache, obstetric pain, gynecological pain, or chemotherapy-induced pain.
  • peripheral or central neuropathic pain inflammatory pain, migraine-related pain, headache-related pain, irritable bowel syndrome-related pain, fibromyalgia-related pain, arthritic pain, skeletal pain, joint pain, gastrointestinal pain, muscle pain, angina pain, facial pain, pelvic pain, claudication, postoperative pain, post traumatic pain, tension-type headache, obstetric pain, gynecological pain, or chemotherapy-induced pain.
  • the invention features a method of reducing pain sensitivity in a subject by administering a compound (e.g., an effective amount) of the first aspect to a subject.
  • a compound e.g., an effective amount
  • the invention features a method of treating (e.g., prophylactically) a metabolic disorder in a subject.
  • the method includes administering a compound of the first aspect of the invention to a subject in an amount sufficient to treat the metabolic disorder.
  • the metabolic disorder may be diabetes (e.g., Type I or Type II), obesity, diabetes as a consequence of obesity, hyperglycemia, dyslipidemia, hypertriglyceridemia, syndrome X, insulin resistance, impaired glucose tolerance (IGT), diabetic dyslipidemia, hyperlipidemia, a cardiovascular disease, or hypertension.
  • the subject may be overweight, obese, or bulimic.
  • the invention features a method of treating (e.g., prophylactically) a disorder selected from the group consisting of anxiety, obsessive- compulsive disorder, Tourette's syndrome, movement disorder, aggression, psychosis, seizures, panic attacks, hysteria, sleep disorders, Alzheimer's disease, and Parkinson's disease.
  • the method includes administering a compound of the first aspect of the invention to a subject in an amount sufficient to treat or prevent the disorder.
  • the psychosis may be schizophrenia.
  • the invention features a method of treating drug addiction or reducing drug abuse in a subject in need thereof.
  • the drug may be a psychostimulant such as amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine, nicotine, cocaine, methylphenidate, or arecoline.
  • the drug is alcohol.
  • the invention features a method of modulating (e.g., increasing or decreasing) blood pressure in a subject (e.g., a subject suffering from either hypertension or hypotension).
  • the amount sufficient may be less than 90%, 75%, 50%, 40%, 30%, 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.1% of the amount required for an equivalent dose of the polypeptide therapeutic (e.g., any described herein) when not conjugated to the peptide vector.
  • the amount sufficient may reduce a side effect as compared to PATENT
  • ATTORNEY DOCKET NO. V82774W0 administration of an effective amount of the polypeptide therapeutic when not conjugated to the peptide vector.
  • the subject may be a mammal such as a human.
  • the peptide vector may be a polypeptide substantially identical to any of the sequences set Table 1, or a fragment thereof.
  • the peptide vector has a sequence of Angiopep-1 (SEQ ID NO:67), Angiopep-2 (SEQ ID NO:97), Angiopep-3 (SEQ ID NO: 107), Angiopep-4a (SEQ ID NO: 108), Angiopep-4b (SEQ ID NO: 109), Angiopep-5 (SEQ ID NO: 110), Angiopep-6 (SEQ ID NO:111), or Angiopep-7 (SEQ ID NO:112)).
  • the peptide vector or conjugate may be efficiently transported into a particular cell type (e.g., any one, two, three, four, or five of liver, lung, kidney, spleen, and muscle) or may cross the mammalian BBB efficiently (e.g., Angiopep-1, -2, -3, -4a, -4b, -5, and -6).
  • a particular cell type e.g., any one, two, three, four, or five of liver, lung, kidney, spleen, and muscle
  • the peptide vector or conjugate is able to enter a particular cell type (e.g., any one, two, three, four, or five of liver, lung, kidney, spleen, and muscle) but does not cross the BBB efficiently (e.g., a conjugate including Angiopep-7).
  • the peptide vector may be of any length, for example, at least 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 25, 35, 50, 75, 100, 200, or 500 amino acids, or any range between these numbers. In certain embodiments, the peptide vector is 10 to 50 amino acids in length.
  • the polypeptide may be produced by recombinant genetic technology or chemical synthesis. Table 1 : Exemplary Peptide Vectors SEQ ID NO:
  • Polypeptides Nos.5, 67, 76, and 91 include the sequences of SEQ ID NOS:5, 67, 76, and 91, respectively, and are amidated at the C-terminus.
  • Polypeptides Nos.107, 109, and 110 include the sequences of SEQ ID NOS:97, 109, and 110, respectively, and are acetylated at the N-terminus.
  • the peptide vector may include an amino acid sequence having the formula:
  • each of Xl -X 19 is, independently, any amino acid (e.g., a naturally occurring amino acid such as Ala, Arg, Asn, Asp, Cys, GIn, GIu, GIy, His, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and VaI) or absent and at least one (e.g., 2 or 3) of Xl, XlO, and Xl 5 is arginine.
  • a naturally occurring amino acid such as Ala, Arg, Asn, Asp, Cys, GIn, GIu, GIy, His, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and VaI
  • X7 is Ser or Cys; or XlO and Xl 5 each are independently Arg or Lys.
  • the residues from Xl through X 19, inclusive are substantially identical to any of the amino acid sequences of any one of SEQ ID NOS:1-105 and 107-116 (e.g., Angiopep-1, Angiopep-2, Angiopep-3, Angiopep-4a, Angiopep-4b, Angiopep-5, Angiopep-6, and Angiopep-7).
  • at least one (e.g., 2, 3, 4, or 5) of the amino acids X1-X19 is Arg.
  • the polypeptide has one or more additional cysteine residues at the N- terminal of the polypeptide, the C-terminal of the polypeptide, or both.
  • the peptide vector or polypeptide therapeutic is modified (e.g., as described herein).
  • the peptide or polypeptide may be amidated, acetylated, or both. Such modifications may be at the amino or carboxy terminus of the polypeptide.
  • the peptide or polypeptide may also include peptidomimetics (e.g., those described herein) of any of the polypeptides described herein.
  • the peptide or polypeptide may be in a multimeric form, for example, dimeric form (e.g., formed by disulfide bonding through cysteine residues).
  • the peptide vector or polypeptide therapeutic (e.g., neurotensin) has an amino acid sequence described herein with at least one amino acid substitution (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 substitutions), insertion, or deletion or is substantially identical to an amino acid sequence described herein.
  • the peptide or polypeptide may contain, for example, 1 to 12, 1 to 10, 1 to 5, or 1 to 3 amino acid substitutions, for example, 1 to 10 (e.g., to 9, 8, 7, 6, 5, 4, 3, 2) amino acid substitutions.
  • the amino acid substitution(s) may be conservative or non- conservative.
  • the peptide vector may have an arginine at one, two, or three of the positions corresponding to positions 1, 10, and 15 of the amino acid sequence of any of SEQ ID NO: 1, Angiopep-1, Angiopep-2, Angiopep-3, Angiopep- 4a, Angiopep-4b, Angiopep-5, Angiopep-6, and Angiopep-7.
  • the polypeptide therapeutic may have a cysteine or lysine substitution or addition at any position (e.g., a lysine substitution at the N- or C-terminal position).
  • the compound may specifically exclude a polypeptide including or consisting of any of SEQ ID NOS:1-105 and 107-116 (e.g., Angiopep-1 , Angiopep-2, Angiopep-3, Angiopep-4a, Angiopep-4b, Angiopep-5, Angiopep-6, and Angiopep-7).
  • the polypeptides and conjugates of the invention exclude the polypeptides of SEQ ID NOs: 102, 103, 104, and 105.
  • the linker (X) may be any linker known in the art or described herein.
  • the linker is a covalent bond (e.g., a peptide bond), a chemical linking agent (e.g., those described herein), an amino acid or a peptide (e.g., 2, 3, 4, 5, 8, 10, or more amino acids).
  • the linker has the formula: PATENT
  • n is an integer between 2 and 15 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, or
  • peptide vector is meant a compound or molecule such as a polypeptide or a polypeptide mimetic that can be transported into a particular cell type (e.g., liver, lungs, kidney, spleen, or muscle) or across the BBB.
  • the vector may be attached to (covalently or not) or conjugated to an agent and thereby may be able to transport the agent into a particular cell type or across the BBB.
  • the vector may bind to receptors present on cancer cells or brain endothelial cells and thereby be transported into the cancer cell or across the BBB by transcytosis.
  • the vector may be a molecule for which high levels of transendothelial transport may be obtained, without affecting the cell or BBB integrity.
  • the vector may be a polypeptide or a peptidomimetic and may be naturally occurring or produced by chemical synthesis or recombinant genetic technology.
  • neurotensin receptor agonist a compound (e.g., a polypeptide) capable of activating at least one neurotensin receptor as compared to a control compound.
  • Neurotensin receptor activities include production of inositol phosphate.
  • substantially identical is meant a polypeptide or nucleic acid exhibiting at least 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 85%, 90%, 95%, or even 99% identity to a reference amino acid or nucleic acid sequence.
  • the length of comparison sequences will generally be at least 4 (e.g., at least 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 50, or 100) amino acids.
  • the length of comparison sequences will generally be at least 60 nucleotides, preferably at least 90 nucleotides, and more preferably at least 120 nucleotides, or full length. It is to be understood herein that gaps may be found between the amino acids of an analogs that are identical or similar to amino acids of the original polypeptide. The gaps may include no amino acids, one or more amino acids that are not identical or similar to the original polypeptide. Biologically active analogs of the vectors (polypeptides) of the invention are encompassed herewith. Percent identity may be PATENT
  • ATTORNEY DOCKET NO. V82774W0 determined, for example, with n algorithm GAP, BESTFIT, or FASTA in the Wisconsin Genetics Software Package Release 7.0, using default gap weights.
  • treating a disease, disorder, or condition in a subject is meant reducing at least one symptom of the disease, disorder, or condition by administrating a therapeutic agent to the subject.
  • treating prophylactically a disease, disorder, or condition in a subject is meant reducing the frequency of occurrence or severity of (e.g., preventing) a disease, disorder or condition by administering to the subject a therapeutic agent to the subject prior to the appearance of a disease symptom or symptoms.
  • a subject who is being treated for a particular condition is one who a medical practitioner has diagnosed as having that condition. Diagnosis may be performed by any suitable means, such as those described herein.
  • a subject in whom the development of the condition is being treated prophylactically may or may not have received such a diagnosis.
  • subject of the invention may have been subjected to standard tests or may have been identified, without examination, as one at high risk due to the presence of one or more risk factors.
  • a metabolic disorder any pathological condition resulting from an alteration in a subject's metabolism. Such disorders include those resulting from an alteration in glucose homeostasis resulting, for example, in hyperglycemia.
  • an alteration in glucose levels is typically an increase in glucose levels by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or even 100% relative to such levels in a healthy individual.
  • Metabolic disorders include obesity and diabetes (e.g., diabetes type I, diabetes type II, MODY, and gestational diabetes), satiety, and endocrine deficiencies of aging.
  • “subject” is meant a human or non-human animal (e.g., a mammal).
  • equivalent dosage is meant the amount of a compound of the invention required to achieve the same molar amount of the peptide therapeutic in the compound of the invention, as compared to the unconjugated polypeptide therapeutic.
  • the equivalent dosage of 1.0 ⁇ g neurotensin is about 2.5 ⁇ g of the neurotensin/Angiopep-2 -CyS-NH 2 conjugate described herein.
  • polypeptide which is "efficiently transported across the BBB” is meant a polypeptide that is able to cross the BBB at least as efficiently as Angiopep-6 (i.e., PATENT
  • polypeptide or compound which is "efficiently transported to a particular cell type” is meant that the polypeptide or compound is able to accumulate (e.g., either due to increased transport into the cell, decreased efflux from the cell, or a combination thereof) in that cell type to at least a 10% (e.g., 25%, 50%, 100%, 200%, 500%, 1 ,000%, 5,000%, or 10,000%) greater extent than either a control substance, or, in the case of a conjugate, as compared to the unconjugated agent.
  • a 10% e.g., 25%, 50%, 100%, 200%, 500%, 1 ,000%, 5,000%, or 10,000% greater extent than either a control substance, or, in the case of a conjugate, as compared to the unconjugated agent.
  • Figures IA and IB are chromatograms showing the ECMS-Neurotensin compound (ECMS-NT) before ( Figure IA) and after ( Figure IB) purification using the analytical method described in the examples.
  • Figure 2 is a chromatogram showing purification of ECMS-NT on an AKTA- explorer with column filled with 30 ml of 30RPC resin.
  • Figures 3A and 3B are chromatograms showing a neurotensin-Angiopep-2- Cys amide conjugate (NT-AN2Cys-NH 2 or NT-An2) before ( Figure 3A) and after ( Figure 3B) purification. These chromatograms were generated using the analytical method described in the examples.
  • Figure 4 is a chromatogram showing purification of NT-An2 on an AKTA- explorer with column filled with 30 ml of 30RPC resin.
  • Figure 5 is a graph showing hypothermia induction by NT-An2. Mice received saline (control), NT (1 mg/kg) or NT-An2 at 2.5 mg/kg or 5.0 mg/kg (equivalent to 1 and 2 mg/kg doses of NT). Rectal temperature was monitored 90 minutes following intravenous injection. PATENT
  • Figure 6 is a graph showing the effect of body temperature in mice upon administration of 5, 15, or 20 mg/kg of NT-An2.
  • Figure 7 is a graph showing the effect of body temperature in mice upon administration of 5, 10, or 20 mg/kg of a different preparation of NT-An2.
  • Figure 8 is a graph showing in situ brain perfusion of NT and NT-An2.
  • mice brains were perfused in the carotid artery with either [ 125 I]-NT or the [ 125 I]-NT-An2 derivative in Krebs buffer for the indicated times. After the indicated times, brains were further perfused for 30 sec to washout the excess of both compound. Both [ 125 I]-NT or [ l25 I]-NT-An2 derivative in brain were quantified using a beta counter. Results are expressed in terms of brain volume of distribution (ml/ 100 g) as a function of time.
  • Figure 9 is a graph showing brain compartmentation of NT and NT-An2 after in situ brain perfusion as described for Figure 6. Brain capillary depletion was performed using Dextran following standard procedures. Both [ 125 I]-NT or [ 125 I]-NT- An2 derivative present in brain, capillaries, and parenchyma were quantified and volume of distribution (ml/100 g/2 min) is reported.
  • Figure 10 is a graph showing body temperature of mice receiving a bolus 5 mg/kg injection of the NT-An2, followed one hour later by a 2.5 hour infusion of NT- An2 at a rate of 5 mg/kg/30 min (i.e., 10 mg/kg/hr).
  • Figure 11 is a graph showing body temperature of a rat receiving an intravenous bolus injection of 20 mg/kg NT-An2, followed immediately by a 20 mg/kg/hr infusion of NT-An2 for 3.5 hours.
  • Figure 12 is a graph showing body temperature of mice receiving an intravenous bolus injection of 20 mg/kg NT-An2, followed immediately by a 20 mg/kg/hr infusion of NT-An2, which was increased to 40 mg/kg/hr after 2.5 hours.
  • Figure 13 is a graph showing body temperature of rats receiving an intravenous bolus injection of 20 mg/kg NT-An2, followed immediately by a 20 mg/kg/hr infusion of NT-An2.
  • Figure 14 is a graph showing body temperature of ratings receiving an intravenous bolus injection of 40 mg/kg NT-An2, followed immediately by a 40 mg/kg/hr infusion of NT-An2. This resulted in sustained reduction in body temperature for the 12 hour duration of the experiment.
  • Figure 15 is a graph showing latency in the hot plate test in mice of the paw licking response in control mice (left), mice receiving 20 mg/kg NT-An2 (center), and mice receiving 1 mg/kg buprenorphine (right) just prior to and 15 minutes following administration of the compound.
  • Figure 16 is a graph showing body temperature of mice receiving a bolus intravenous 7.5 mg/kg injection of NT(8-13), Ac-Lys-NT(8-13), Ac-LyS-[D- Tyr 1 ']NT(8-13), pGlu-NT(8-l 3), or a control. From among these analogs, Ac-Lys- [D-Tyr 11 JNT(S-13) was observed to produce the greatest reduction in body temperature.
  • Figure 17 is a graph showing body temperature of mice receiving a bolus intravenous injection of a control, NT, NT-An2, NT(8-13)-An2, and Ac-LyS-[D- Tyr ⁇ ]NT(8-13)-An2. The greatest reduction in body temperature was observed for NT-An2 and Ac-Lys-[D-Tyr"]NT(8-13)-An2 conjugates.
  • Figure 18 is a graph showing body temperature of mice receiving a bolus intravenous injection of Ac-Lys-[D-Tyr"]NT(8-13) (1 mg/kg) or Ac-LyS-[D-
  • Figure 19 is a graph showing body temperature of a mouse receiving a 6.25 mg/kg bolus intravenous injection of the Ac-Lys-[D-Tyr"]NT(8-13)-An2 conjugate followed 60 minutes later by a 6.25 mg/kg/hr infusion of the conjugate.
  • Figure 20 is a graph showing binding of radiolabeled NT ([ 3 H]-NT) to HT29 cells that express the NTSRl in the presence or absence of 40 nM of NT at 4 0 C or 37 0 C.
  • Figure 21 is a graph showing binding Of [ 3 H]-NT to HT29 cells in the presence of NT at concentrations ranging from 0.4 nM to 40 nM.
  • Figure 22 is graph showing binding Of [ 3 H]-NT to HT29 cells in the presence of NT or Ac-Lys-[D-Tyr"]NT(8-13).
  • ATTORNEY DOCKET NO. V82774W0 causing a neurotensin response, such as a reduction in body temperature, as compared to unconjugated neurotensin.
  • a neurotensin response such as a reduction in body temperature
  • the compounds of the invention exhibit higher response, lower doses of the conjugated peptides can be effectively, and may be used to reduce or eliminate side effects. Alternatively, the observed increased efficacy can result in a greater therapeutic effect using higher doses.
  • these compounds unlike certain prior hypothermic techniques, are capable of rapidly inducing a sustainable hypothermic response (e.g., over a period of at least 3, 4, 5, 6, 8, 10, 12, 15, 18, 21, 24, 30, 36, or 48 hours) without inducing shivering.
  • Neurotensin is a 13 amino acid peptide found in the central nervous system and in the gastrointestinal tract. In brain, NT is associated with dopaminergic receptors and other neurotransmitter system. Peripheral NT acts as a paracrine and endocrine peptide on both the digestive and cardiovascular systems. To exert its biological effects in the brain NT has to be injected or delivered directly to the brain because NT does not cross the BBB and is rapidly degraded by peptidases following systematic administration.
  • NT receptors Preclinical pharmacological studies, most of which involve direct injection of NT into the brain, strongly suggest that an agonist of NT receptors would be clinically useful for the treatment of neuropsychiatric conditions including psychosis, schizophrenia, Parkinson's disease, pain, and the abuse of psychostimulants.
  • intraventricular injection of NT led to hypothermia and analgesia in antinociception experiments.
  • the peptide therapeutic may be neurotensin or analog thereof.
  • Human neurotensin is a thirteen amino acid peptide having the sequence QLYENKPRRPYIL.
  • exemplary neurotensin analogs include (VIP-neurotensin) hybrid antagonist, acetylneurotensin(8-13), JMV 1193, KK 13 peptide, neuromedin N, neuromedin N precursor, neurotensin(l-l ⁇ ), neurotensin(l-l 1), neurotensin(l-13), neurotensin 1-6), neurotensin 1-8), neurotensin(8-13), Asp(12)-neurotensin(8-13), Asp(13)- neurotensin(8-13), Lys(8)-neurotensin(8-13), N-methyl-Arg(8)-Lys(9)-neo-Trp(l I)- neo-Leu(12)-neurotensin(8-13), neurotensin(9-13), neurotensin
  • neurotensin analogs include NT64L [L-neo-T ⁇ l 1]NT(8-13), NT72D [D-Lys9,D-neo-Trpl l,tert-Leul2]NT(9-13), NT64D [D-neo-T ⁇ l 1]NT(8-13), NT73L [D-Lys9,L-neo-Trpl 1]NT(9-13), NT65L [L-neo-T ⁇ l 1, tert-Leul2]NT(8-13), NT73D [D-Lys9,D-neo-T ⁇ l 1]NT(9-13), NT65D [D-neo-T ⁇ l 1, tert-Leul2]NT(8-13), NT74L [DAB9,L-neo-T ⁇ l l,tert-Leul2]NT(9-13), NT66L [D-Lys8, L-neo-T ⁇ l 1,
  • Still other NT analogs include guinea pig NT, [GIn 4 JNT, [D-Trp”]NT, NT(9- 13), frog NT, [GIn 4 JNT, [D-Phe”]NT, [D-T ⁇ "]NT, [D-Tyr”]NT, Ac-NT(8-13), [Lys 8 ' 9 ]NT(8-13), [3,5-diBr-Tyr”]NT, N ⁇ -Acetyl-NT(8-13), N ⁇ ,N ⁇ -di-Boc- [Lys 9 ]NT(9-13) methyl ester, Boc-[Lys 9 ]NT(9-13)-methyl ester, [T ⁇ H ]NT, [Dab 9 ]NT (8-13), [LyS 9 ZIYp 1 ',GIu 12 JNT(S- 13) (Cyclo(-Arg-Lys-Pro-T ⁇ -Glu)-Leu- OH), [Lys 8
  • Patent Application Publication 2009/0062212 D-Lys L-Arg L-Pro L-Tyr L-IIe L-Leu, L-Arg D-Lys L- Pro L-Tyr L-IIe L-Leu, L-Arg D-Arg L-Pro L-Tyr L-IIe L-Leu, L-Arg L-Arg L-Pro L-Tyr L-IIe D-Leu, L-Arg L-Arg GIy L-Tyr L-IIe L-Leu, L-Arg L-Arg L-Pro L-AIa L-IIe L-Leu, L-Arg L-Arg L-Arg L-Arg L-Pro L-Tyr L-Leu L-Leu, L-Arg L-Arg L-Arg L-Arg L-Pro L-Tyr L- VaI L-Leu, D-Arg L-Arg L-Pro L-Tyr L-IIe L-Leu, D-Arg D-Arg L-Pro L-Tyr L-
  • BPA benzoylphenylalanine
  • CHA cyclohexylalanine
  • DAB diaminobutyric acid
  • DAP diaminoproprionic acid
  • homoArg homoarginine
  • Orn ornithine
  • NaI naphthyl-alanine
  • Pip 1-pipecolinic acid
  • neo-T ⁇ a regio- isomer of the native tryptophan (Fauq et al., Tetrahedron: Asymmetry 9:4127-34 (1998))
  • TIC l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
  • neurotensin analogs include those with modified amino acids (e.g., any of those described herein).
  • the neurotensin analog may be selective for NTRl, NTR2, or NTR3 (e.g., may bind to or activate one of NTRl, NTR2, or NTR3 at least 2, 5, 10, 50, 100, 500, 1000, 5000, 10,000, 50,000, or 100,000 greater) as compared to at least one of the other NTR receptors or both.
  • polypeptide therapeutics described herein may be modified (e.g., as described herein or as known in the art).
  • the polypeptide can be bound to a polymer to increase its molecular weight.
  • Exemplary polymers include polyethylene glycol polymers, polyamino acids, PATENT
  • ATTORNEY DOCKET NO. V82774W0 albumin gelatin, succinyl-gelatin, (hydroxypropyl)-methacrylamide, fatty acids, polysaccharides, lipid amino acids, and dextran.
  • polypeptide is modified by addition of albumin (e.g., human albumin), or an analog or fragment thereof, or the Fc portion of an immunoglobulin.
  • albumin e.g., human albumin
  • analog or fragment thereof or the Fc portion of an immunoglobulin.
  • the polypeptide is modified by addition of a lipophilic substituent, as described in PCT Publication WO 98/08871.
  • the lipophilic substituent may include a partially or completely hydrogenated cyclopentanophenathrene skeleton, a straight-chain or branched alkyl group; the acyl group of a straight-chain or branched fatty acid (e.g., a group including CH 3 (CH 2 ) n CO- or HOOC(CH 2 ) m CO-, where n or m is 4 to 38); an acyl group of a straight-chain or branched alkane ⁇ , ⁇ - dicarboxylic acid; CH 3 (CH 2 ) p ((CH 2 ) q ,COOH)CHNH-CO(CH 2 ) 2 CO-, where p and q are integers and p+q is 8 to 33; CH 3 (CH 2 ) r CO-NHCH(COOH)(CH 2 ) 2 CO-, where
  • the polypeptide therapeutic is modified by addition of a chemically reactive group such as a maleimide group, as described in U.S. Patent No. 6,593,295.
  • a chemically reactive group such as a maleimide group
  • these groups can react with available reactive functionalities on blood components to form covalent bonds and can extending the effective therapeutic in vivo half-life of the modified polypeptides.
  • a chemically reactive group a wide variety of active carboxyl groups (e.g., esters) where the hydroxyl moiety is physiologically acceptable at the levels required to modify the peptide.
  • N-hydroxysuccinimide (NHS), N-hydroxy-sulfosuccinimide (sulfo- NHS), maleimide-benzoyl-succinimide (MBS), gamma-maleimido-butyryloxy succinimide ester (GMBS), maleimido propionic acid (MPA) maleimido hexanoic acid (MHA), and maleimido undecanoic acid (MUA).
  • NHS N-hydroxysuccinimide
  • MMS gamma-maleimido-butyryloxy succinimide ester
  • MHA maleimido propionic acid
  • MHA maleimido hexanoic acid
  • MHA maleimido undecanoic acid
  • Primary amines are the principal targets for NHS esters. Accessible ⁇ -amine groups present on the N-termini of proteins and the ⁇ -amine of lysine react with NHS esters. An amide bond is formed when the NHS ester conjugation reaction reacts with primary amines releasing N-hydroxysuccinimide.
  • succinimide containing reactive groups are herein referred to as succinimidyl groups.
  • the functional group on the protein will be a thiol group and the chemically reactive group will be a maleimido-containing group such as gamma- maleimide-butrylamide (GMBA or MPA). Such maleimide containing groups are referred to herein as maleido groups.
  • the maleimido group is most selective for sulfhydryl groups on peptides when the pH of the reaction mixture is 6.5-7.4.
  • the rate of reaction of maleimido groups with sulfhydryls e.g., thiol groups on proteins such as serum albumin or IgG
  • sulfhydryls e.g., thiol groups on proteins such as serum albumin or IgG
  • a stable thioether linkage between the maleimido group and the sulfhydryl is formed, which cannot be cleaved under physiological conditions.
  • the compounds of the invention can feature any of polypeptides described herein, for example, any of the peptides described in Table 1 (e.g., Angiopep-1 or Angiopep-2), or a fragment or analog thereof.
  • the polypeptide may have at least 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or even 100% identity to a polypeptide described herein.
  • the polypeptide may have one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) substitutions relative to one of the sequences described herein. Other modifications are described in greater detail below.
  • the invention also features fragments of these polypeptides (e.g., a functional fragment).
  • the fragments are capable of efficiently being transported to or accumulating in a particular cell type (e.g., liver, eye, lung, kidney, or spleen) or are efficiently transported across the BBB.
  • Truncations of the polypeptide may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, or more amino acids from either the N-terminus of the polypeptide, the C-terminus of the polypeptide, or a combination thereof.
  • Other fragments include sequences where internal portions of the polypeptide are deleted.
  • Additional polypeptides may be identified by using one of the assays or methods described herein.
  • a candidate polypeptide may be produced by conventional peptide synthesis, conjugated with paclitaxel and administered to a laboratory animal.
  • a biologically-active polypeptide conjugate may be identified, for example, based on its ability to increase survival of an animal injected with tumor cells and treated with the conjugate as compared to a control which has not been treated with a conjugate (e.g., treated with the unconjugated agent).
  • a biologically active polypeptide may be identified based on its location in the parenchyma in an in situ cerebral perfusion assay. Assays to determine accumulation in other tissues may be performed as well.
  • Labeled conjugates of a polypeptide can be administered to an animal, and accumulation in different organs can be measured.
  • a polypeptide conjugated to a detectable label e.g., a near-IR fluorescence spectroscopy label such as Cy5.5
  • a detectable label e.g., a near-IR fluorescence spectroscopy label such as Cy5.5
  • a polypeptide conjugated to a detectable label allows live in vivo visualization.
  • a polypeptide can be administered to an animal, and the presence of the polypeptide in an organ can be detected, thus allowing determination of the rate and amount of accumulation of the polypeptide in the desired organ.
  • the polypeptide can be labelled with a radioactive isotope (e.g., 125 I). The polypeptide is then administered to an animal. After a period of time, the animal is sacrificed and the organs are extracted.
  • a radioactive isotope e.g., 125 I
  • the amount of radioisotope in each organ can then be measured using any means known in the art.
  • the amount of a labeled candidate polypeptide in a particular organ relative to the amount of a labeled control polypeptide, the ability of the candidate polypeptide to access and accumulate in a particular tissue can be ascertained.
  • Appropriate negative controls include any peptide or polypeptide known not to be efficiently transported into a particular cell type (e.g., a peptide related to Angiopep that does not cross the BBB, or any other peptide).
  • Other examples of aprotinin analogs may be found by performing a protein PATENT
  • BLAST Genbank: www.ncbi.nlm.nih.gov/BLAST/
  • exemplary aprotinin analogs are also found under accession Nos. CAA37967 (GI:58005) and 1405218C (GI:3604747).
  • the peptide vectors and polypeptide therapeutics used in the invention may have a modified amino acid sequence.
  • the modification does not destroy significantly a desired biological activity (e.g., ability to cross the BBB or neurotensin agonist activity).
  • the modification may reduce (e.g., by at least 5%, 10%, 20%, 25%, 35%, 50%, 60%, 70%, 75%, 80%, 90%, or 95%), may have no effect, or may increase (e.g., by at least 5%, 10%, 25%, 50%, 100%, 200%, 500%, or 1000%) the biological activity of the original polypeptide.
  • the modified peptide or polypeptide may have or may optimize a characteristic of a polypeptide, such as in vivo stability, bioavailability, toxicity, immunological activity, immunological identity, and conjugation properties.
  • Modifications include those by natural processes, such as posttranslational processing, or by chemical modification techniques known in the art. Modifications may occur anywhere in a polypeptide including the polypeptide backbone, the amino acid side chains and the amino- or carboxy-terminus. The same type of modification may be present in the same or varying degrees at several sites in a given polypeptide, and a polypeptide may contain more than one type of modification. Polypeptides may be branched as a result of ubiquitination, and they may be cyclic, with or without branching. Cyclic, branched, and branched cyclic polypeptides may result from posttranslational natural processes or may be made synthetically.
  • modifications include pegylation, acetylation, acylation, addition of acetomidomethyl (Acm) group, ADP-ribosylation, alkylation, amidation, biotinylation, carbamoylation, carboxyethylation, esterification, covalent attachment to flavin, covalent attachment to a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of drug, covalent attachment of a marker (e.g., fluorescent or radioactive), covalent attachment of a lipid or lipid derivative, covalent attachment of phosphatidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent crosslinks, formation of cystine, formation of PATENT
  • ATTORNEY DOCKET NO. V82774W0 pyroglutamate formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer-RNA mediated addition of amino acids to proteins such as arginylation and ubiquitination.
  • a modified polypeptide can also include an amino acid insertion, deletion, or substitution, either conservative or non-conservative (e.g., D-amino acids, desamino acids) in the polypeptide sequence (e.g., where such changes do not substantially alter the biological activity of the polypeptide).
  • conservative or non-conservative e.g., D-amino acids, desamino acids
  • the addition of one or more cysteine residues to the amino or carboxy terminus of any of the polypeptides of the invention can facilitate conjugation of these polypeptides by, e.g., disulfide bonding.
  • Angiopep-1 (SEQ ID NO:67), Angiopep-2 (SEQ ID NO:97), or Angiopep-7 (SEQ ID NO: 112) can be modified to include a single cysteine residue at the amino-terminus (SEQ ID NOS: 71, 1 13, and 1 15, respectively) or a single cysteine residue at the carboxy -terminus (SEQ ID NOS: 72, 1 14, and 116, respectively).
  • Amino acid substitutions can be conservative (i.e., wherein a residue is replaced by another of the same general type or group) or non-conservative (i.e., wherein a residue is replaced by an amino acid of another type).
  • a non- naturally occurring amino acid can be substituted for a naturally occurring amino acid (i.e., non-naturally occurring conservative amino acid substitution or a non-naturally occurring non-conservative amino acid substitution).
  • Polypeptides made synthetically can include substitutions of amino acids not naturally encoded by DNA (e.g., non-naturally occurring or unnatural amino acid).
  • non-naturally occurring amino acids include D-amino acids, an amino acid having an acetylaminomethyl group attached to a sulfur atom of a cysteine, a pegylated amino acid, the omega amino acids of the formula NH 2 (CH 2 ) n COOH wherein n is 2-6, neutral nonpolar amino acids, such as sarcosine, t-butyl alanine, t- butyl glycine, N-methyl isoleucine, and norleucine.
  • Phenylglycine may substitute for Tip, Tyr, or Phe; citrulline and methionine sulfoxide are neutral nonpolar, cysteic acid is acidic, and ornithine is basic. Proline may be substituted with hydroxyproline and retain the conformation conferring properties.
  • Analogs may be generated by substitutional mutagenesis and retain the biological activity of the original polypeptide. Examples of substitutions identified as PATENT
  • substitutions are shown in Table 2. If such substitutions result in a change not desired, then other type of substitutions, denominated “exemplary substitutions” in Table 3, or as further described herein in reference to amino acid classes, are introduced and the products screened. Substantial modifications in function or immunological identity are accomplished by selecting substitutions that differ significantly in their effect on maintaining (a) the structure of the polypeptide backbone in the area of the substitution, for example, as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain. Naturally occurring residues are divided into groups based on common side chain properties:
  • polypeptides consisting of naturally occurring amino acids
  • polypeptide analogs are also encompassed by the present invention and can form the peptide vectors or peptide therapeutics used in the compounds of the invention.
  • Polypeptide analogs are commonly used in the pharmaceutical industry as non-peptide drugs with properties analogous to those of the template polypeptide.
  • the non-peptide compounds are termed "peptide mimetics" or peptidomimetics (Fauchere et al., Infect. Immun. 54:283-287,1986 and Evans et al., J. Med. Chem. 30: 1229-1239, 1987).
  • Peptide mimetics that are structurally related to therapeutically useful peptides or polypeptides may be used to produce an equivalent or enhanced therapeutic or prophylactic effect.
  • ATTORNEY DOCKET NO. V82774WO production greater chemical stability, enhanced pharmacological properties (e.g., half-life, absorption, potency, efficiency), reduced antigenicity, and others.
  • peptide vectors described herein may efficiently cross the BBB or target particular cell types (e.g., those described herein), their effectiveness may be reduced by the presence of proteases.
  • the effectiveness of the polypeptide therapeutics used in the invention may be similarly reduced.
  • Serum proteases have specific substrate requirements, including L-amino acids and peptide bonds for cleavage.
  • exopeptidases which represent the most prominent component of the protease activity in serum, usually act on the first peptide bond of the polypeptide and require a free N-terminus (Powell et al., Pharm. Res. 10:1268- 1273, 1993). In light of this, it is often advantageous to use modified versions of polypeptides.
  • the modified polypeptides retain the structural characteristics of the original L-amino acid polypeptides, but advantageously are not readily susceptible to cleavage by protease and/or exopeptidases.
  • Systematic substitution of one or more amino acids of a consensus sequence with D-amino acid of the same type e.g., an enantiomer; D-lysine in place of L- lysine
  • D-amino acid of the same type e.g., an enantiomer; D-lysine in place of L- lysine
  • a polypeptide derivative or peptidomimetic as described herein may be all L-, all D-, or mixed D, L polypeptides.
  • Reverse-D polypeptides are polypeptides containing D-amino acids, arranged in a reverse sequence relative to a polypeptide containing L-amino acids.
  • the C-terminal residue of an L-amino acid polypeptide becomes N-terminal for the D-amino acid polypeptide, and so forth.
  • Reverse D-polypeptides retain the same tertiary conformation and therefore the same activity, as the L-amino acid polypeptides, but are more stable to enzymatic degradation in vitro and in vivo, and thus have greater therapeutic efficacy than the original polypeptide (Brady and Dodson, Nature 368:692-693, 1994 and Jameson et al., Nature 368:744-746, 1994).
  • constrained polypeptides comprising a consensus sequence or a substantially identical consensus sequence variation may be generated by methods well known in the art (Rizo et al., Ann. Rev. Biochem. 61 :387-418, 1992).
  • constrained polypeptides may be generated by adding cysteine residues PATENT
  • ATTORNEY DOCKET NO. V82774W0 capable of forming disulfide bridges and, thereby, resulting in a cyclic polypeptide.
  • Cyclic polypeptides have no free N- or C-termini. Accordingly, they are not susceptible to proteolysis by exopeptidases, although they are, of course, susceptible to endopeptidases, which do not cleave at polypeptide termini.
  • the amino acid sequences of the polypeptides with N-terminal or C-terminal D-amino acids and of the cyclic polypeptides are usually identical to the sequences of the polypeptides to which they correspond, except for the presence of N-terminal or C-terminal D-amino acid residue, or their circular structure, respectively.
  • a cyclic derivative containing an intramolecular disulfide bond may be prepared by conventional solid phase synthesis while incorporating suitable S- protected cysteine or homocysteine residues at the positions selected for cyclization such as the amino and carboxy termini (Sah et al., J. Pharm. Pharmacol. 48:197, 1996).
  • cyclization can be performed either (1) by selective removal of the S-protecting group with a consequent on-support oxidation of the corresponding two free SH-functions, to form a S-S bonds, followed by conventional removal of the product from the support and appropriate purification procedure or (2) by removal of the polypeptide from the support along with complete side chain de-protection, followed by oxidation of the free SH-functions in highly dilute aqueous solution.
  • the cyclic derivative containing an intramolecular amide bond may be prepared by conventional solid phase synthesis while incorporating suitable amino and carboxyl side chain protected amino acid derivatives, at the position selected for cyclization.
  • the cyclic derivatives containing intramolecular -S-alkyl bonds can be prepared by conventional solid phase chemistry while incorporating an amino acid residue with a suitable amino-protected side chain, and a suitable S-protected cysteine or homocysteine residue at the position selected for cyclization.
  • Another effective approach to confer resistance to peptidases acting on the N- terminal or C-terminal residues of a polypeptide is to add chemical groups at the polypeptide termini, such that the modified polypeptide is no longer a substrate for the peptidase.
  • One such chemical modification is glycosylation of the polypeptides at either or both termini.
  • Certain chemical modifications, in particular N-terminal glycosylation, have been shown to increase the stability of polypeptides in human serum (Powell et al., Pharm. Res. 10: 1268-1273, 1993).
  • ATTORNEY DOCKET NO. V82774WO modifications which enhance serum stability include, but are not limited to, the addition of an N-terminal alkyl group, consisting of a lower alkyl of from one to twenty carbons, such as an acetyl group, and/or the addition of a C-terminal amide or substituted amide group.
  • the present invention includes modified polypeptides consisting of polypeptides bearing an N-terminal acetyl group and/or a C-terminal amide group.
  • polypeptide derivatives containing additional chemical moieties not normally part of the polypeptide, provided that the derivative retains the desired functional activity of the polypeptide.
  • examples of such derivatives include (1) N-acyl derivatives of the amino terminal or of another free amino group, wherein the acyl group may be an alkanoyl group (e.g., acetyl, hexanoyl, octanoyl) an aroyl group (e.g., benzoyl) or a blocking group such as F-moc (fluorenylmethyl-O-CO-); (2) esters of the carboxy terminal or of another free carboxy or hydroxyl group; (3) amide of the carboxy- terminal or of another free carboxy 1 group produced by reaction with ammonia or with a suitable amine; (4) phosphorylated derivatives.
  • the acyl group may be an alkanoyl group (e.g., acetyl, hexanoyl, octanoy
  • polypeptide sequences which result from the addition of additional amino acid residues to the polypeptides described herein are also encompassed in the present invention. Such longer polypeptide sequences can be expected to have the same biological activity and specificity (e.g., cell tropism) as the polypeptides described above. While polypeptides having a substantial number of additional amino acids are not excluded, it is recognized that some large polypeptides may assume a configuration that masks the effective sequence, thereby preventing binding to a target (e.g., a member of the LRP receptor family such as LRP or LRP2). These derivatives could act as competitive antagonists. Thus, while the present invention encompasses polypeptides or derivatives of the polypeptides described herein having an extension, desirably the extension does not destroy the cell targeting activity of the polypeptides or its derivatives.
  • a target e.g., a member of the LRP receptor family such as LRP or LRP2
  • derivatives included in the present invention are dual polypeptides consisting of two of the same, or two different polypeptides, as described herein, covalently linked to one another either directly or through a spacer, such as by a short stretch of alanine residues or by a putative site for proteolysis (e.g., by cathepsin, see e.g., U.S. Patent No. 5,126,249 and European Patent No. 495 049).
  • Multimers of the PATENT are dual polypeptides consisting of two of the same, or two different polypeptides, as described herein, covalently linked to one another either directly or through a spacer, such as by a short stretch of alanine residues or by a putative site for proteolysis (e.g., by cathepsin, see e.g., U.S. Patent No. 5,126,249 and European Patent No. 495 049).
  • ATTORNEY DOCKET NO. V82774W0 polypeptides described herein consist of a polymer of molecules formed from the same or different polypeptides or derivatives thereof.
  • the present invention also encompasses polypeptide derivatives that are chimeric or fusion proteins containing a polypeptide described herein, or fragment thereof, linked at its amino- or carboxy-terminal end, or both, to an amino acid sequence of a different protein.
  • a chimeric or fusion protein may be produced by recombinant expression of a nucleic acid encoding the protein.
  • a chimeric or fusion protein may contain at least 6 amino acids shared with one of the described polypeptides which desirably results in a chimeric or fusion protein that has an equivalent or greater functional activity.
  • non-peptidyl compounds generated to replicate the backbone geometry and pharmacophore display (peptidomimetics) of the polypeptides described herein often possess attributes of greater metabolic stability, higher potency, longer duration of action, and better bioavailability.
  • Peptidomimetics compounds can be obtained using any of the numerous approaches in combinatorial library methods known in the art, including biological libraries, spatially addressable parallel solid phase or solution phase libraries, synthetic library methods requiring deconvolution, the 'one-bead one-compound' library method, and synthetic library methods using affinity chromatography selection.
  • the biological library approach is limited to peptide libraries, while the other four approaches are applicable to peptide, non-peptide oligomer, or small molecule libraries of compounds (Lam, Anticancer Drug Des. 12: 145, 1997). Examples of methods for the synthesis of molecular libraries can be found in the art, for example, in: DeWitt et al. (Proc. Natl. Acad.
  • polypeptide as described herein can be isolated and purified by any number of standard methods including, but not limited to, differential solubility (e.g., precipitation), centrifugation, chromatography (e.g., affinity, ion exchange, and size exclusion), or by any other standard techniques used for the purification of peptides, peptidomimetics, or proteins.
  • differential solubility e.g., precipitation
  • centrifugation e.g., centrifugation
  • chromatography e.g., affinity, ion exchange, and size exclusion
  • the functional properties of an identified polypeptide of interest may be evaluated using any functional assay known in the art. Desirably, assays for evaluating downstream receptor function in intracellular signaling are used (e.g., cell proliferation).
  • the peptidomimetics compounds of the present invention may be obtained using the following three-phase process: (1) scanning the polypeptides described herein to identify regions of secondary structure necessary for targeting the particular cell types described herein; (2) using conformational Iy constrained dipeptide surrogates to refine the backbone geometry and provide organic platforms corresponding to these surrogates; and (3) using the best organic platforms to display organic pharmocophores in libraries of candidates designed to mimic the desired activity of the native polypeptide.
  • the three phases are as follows. In phase 1 , the lead candidate polypeptides are scanned and their structure abridged to identify the requirements for their activity. A series of polypeptide analogs of the original are synthesized.
  • phase 2 the best polypeptide analogs are investigated using the conformationally constrained dipeptide surrogates.
  • Indolizidin-2-one, indolizidin-9-one and quinolizidinone amino acids (I 2 aa, I 9 aa and Qaa respectively) are used as platforms for studying backbone geometry of the best peptide candidates.
  • These and related platforms (reviewed in Halab et al., Biopolymers 55:101-122, 2000 and Hanessian et al., Tetrahedron 53: 12789-12854, 1997) may be introduced at specific regions of the polypeptide to orient the pharmacophores in different directions. Biological evaluation of these analogs identifies improved lead polypeptides that mimic the geometric requirements for activity.
  • the platforms from the most active lead polypeptides are used to display organic surrogates of the pharmacophores responsible for activity of the native peptide.
  • the pharmacophores and scaffolds are combined in a parallel synthesis format.
  • Structure function relationships determined from the polypeptides, polypeptide derivatives, peptidomimetics or other small molecules described herein may be used to refine and prepare analogous molecular structures having similar or better properties. Accordingly, the compounds of the present invention also include molecules that share the structure, polarity, charge characteristics and side chain properties of the polypeptides described herein.
  • peptides and peptidomimetics screening assays which are useful for identifying compounds for targeting an agent to particular cell types (e.g., those described herein).
  • the assays of this invention may be developed for low-throughput, high-throughput, or ultra-high throughput screening formats.
  • Assays of the present invention include assays amenable to automation.
  • the polypeptide therapeutic may be bound to the vector peptide either directly (e.g., through a covalent bond such as a peptide bond) or may be bound through a linker.
  • Linkers include chemical linking agents (e.g., cleavable linkers) and peptides.
  • the linker is a chemical linking agent.
  • the polypeptide therapeutic and peptide vector may be conjugated through sulfhydryl groups, amino groups (amines), and/or carbohydrates or any appropriate reactive group.
  • Homobifunctional and heterobifunctional cross-linkers (conjugation agents) are available from many commercial sources. Regions available for cross-linking may be found on the polypeptides of the present invention.
  • the cross-linker may comprise a flexible arm, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, or 15 carbon atoms.
  • cross-linkers include BS3 ([Bis(sulfosuccinimidyl)suberate]; BS3 is a homobifunctional N-hydroxysuccinimide ester that targets accessible primary amines), NHS/EDC (N-hydroxysuccinimide and N-ethyl-
  • NHS/EDC allows for the conjugation of primary amine groups with carboxyl groups
  • sulfo-EMCS [N-e-Maleimidocaproic acid]hydrazide
  • sulfo-EMCS are heterobifunctional reactive groups (maleimide and PATENT
  • NHS-ester that are reactive toward sulfhydryl and amino groups
  • hydrazide most proteins contain exposed carbohydrates and hydrazide is a useful reagent for linking carboxyl groups to primary amines
  • SATA N-succinimidyl-S-acetylthioacetate; SATA is reactive towards amines and adds protected sulfhydryls groups.
  • active carboxyl groups e.g., esters
  • Particular agents include N-hydroxysuccinimide (NHS), N-hydroxy-sulfosuccinimide (sulfo- NHS), maleimide-benzoyl-succinimide (MBS), gamma-maleimido-butyryloxy succinimide ester (GMBS), maleimido propionic acid (MPA) maleimido hexanoic acid (MHA), and maleimido undecanoic acid (MUA).
  • NHS N-hydroxysuccinimide
  • MBS gamma-maleimido-butyryloxy succinimide ester
  • MHA gamma-maleimido-butyryloxy succinimide ester
  • MHA maleimido propionic acid
  • MHA maleimido hexanoic acid
  • MUA maleimido undecanoic acid
  • Primary amines are the principal targets for NHS esters. Accessible ⁇ -amine groups present on the N-termini of proteins and the ⁇ -amine of lysine react with NHS esters. An amide bond is formed when the NHS ester conjugation reaction reacts with primary amines releasing N-hydroxysuccinimide.
  • succinimide containing reactive groups are herein referred to as succinimidyl groups.
  • the functional group on the protein will be a thiol group and the chemically reactive group will be a maleimido-containing group such as gamma- maleimide-butrylamide (GMBA or MPA). Such maleimide containing groups are referred to herein as maleido groups.
  • the maleimido group is most selective for sulfhydryl groups on peptides when the pH of the reaction mixture is 6.5-7.4.
  • the rate of reaction of maleimido groups with sulfhydryls e.g., thiol groups on proteins such as serum albumin or IgG
  • sulfhydryls e.g., thiol groups on proteins such as serum albumin or IgG
  • a stable thioether linkage between the maleimido group and the sulfhydryl can be formed.
  • the linker includes at least one amino acid (e.g., a peptide of at least 2, 3, 4, 5, 6, 7, 10, 15, 20, 25, 40, or 50 amino acids).
  • the linker is a single amino acid (e.g., any naturally occurring amino acid such as Cys).
  • a glycine-rich peptide such as a peptide having the sequence [Gly-Gly-Gly-Gly-Ser] n where n is 1, 2, 3, 4, 5 or 6 is used, as described in U.S. Patent No. 7,271 ,149.
  • a serine-rich peptide linker is used, as described in U.S. Patent No. 5,525,491.
  • Serine rich peptide linkers include those of the formula [X-X-X-X-Gly] y , where up to two of the X are Thr, and PATENT
  • the linker is a single amino acid (e.g., any amino acid, such as GIy or Cys).
  • linkers are succinic acid, Lys, GIu, and Asp, or a dipeptide such as Gly-Lys.
  • the linker is succinic acid
  • one carboxyl group thereof may form an amide bond with an amino group of the amino acid residue
  • the other carboxyl group thereof may, for example, form an amide bond with an amino group of the peptide or substituent.
  • the linker is Lys, GIu, or Asp
  • the carboxyl group thereof may form an amide bond with an amino group of the amino acid residue
  • the amino group thereof may, for example, form an amide bond with a carboxyl group of the substituent.
  • a further linker may be inserted between the ⁇ -amino group of Lys and the substituent.
  • the further linker is succinic acid which, e.g., forms an amide bond with the ⁇ - amino group of Lys and with an amino group present in the substituent.
  • the further linker is GIu or Asp (e.g., which forms an amide bond with the ⁇ -amino group of Lys and another amide bond with a carboxyl group present in the substituent), that is, the substituent is a N ⁇ -acylated lysine residue.
  • Determination of whether a compound has neurotensin agonist activity can be performed using any method known in the art.
  • Activity at the neurotensin receptor can measured, for example, by release of inositol phosphates.
  • Inositol phosphate production from cells expressing a neurotensin receptor e.g., a human or rat receptor
  • Inositol phosphate production from cells expressing a neurotensin receptor e.g., a human or rat receptor
  • an increase in inositol phosphate production indicates the compound to be a neurotensin receptor agonist.
  • ATTORNEY DOCKET NO. V82774W0 measured by prelabeling cells with D-myo-[ 3 H]inositol. Production of [ 3 H]Inositol 1- phosphate is isolated by anion exchange chromatorgraphy.
  • Neurotensin is a 13 amino acid peptide found in the central nervous system and in the gastrointestinal tract. In brain, NT is associated with dopaminergic receptors and other neurotransmitter systems. Peripheral NT acts as a paracrine and endocrine peptide on both the digestive and cardiovascular systems.
  • Various therapeutic applications have been suggested for neurotensin, including psychiatric disorders, metabolic disorder, and pain. Because neurotensin has been shown to modulate neurotransmission in areas of the brain associated with schizophrenia, neurotensin and neurotensin receptor agonists have been proposed as antipsychotic agents.
  • polypeptides described herein are capable of transporting an agent across the BBB
  • the compounds of the invention are also useful for the treatment of neurological diseases such as neurodegenerative diseases or other conditions of the central nervous system (CNS), the peripheral nervous system, or the autonomous nervous system (e.g., where neurons are lost or deteriorate).
  • Neurotensin has been suggested an antipsychotic therapy, and thus may be useful in the treatment of diseases such as schizophrenia and bipolar disorder.
  • Many neurodegenerative diseases are characterized by ataxia (i.e., uncoordinated muscle movements) and/or memory loss.
  • Neurodegenerative diseases include Alexander disease, Alper disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS; i.e., Lou Gehrig's disease), ataxia telangiectasia, Batten disease ( Saintmeyer-Vogt-Sjogren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt- Jakob disease, Huntington's disease, HIV- associated dementia, Kennedy's disease, Krabbe disease, Lewy body dementia,
  • Machado-Joseph disease Spinocerebellar ataxia type 3
  • multiple sclerosis multiple system atrophy
  • narcolepsy neuroborreliosis
  • Parkinson's disease Pelizaeus- Merzbacher disease
  • Pick's disease primary lateral sclerosis, prion diseases, PATENT
  • Refsum's disease Schilder's disease (i.e., adrenoleukodystrophy), schizophrenia, spinocerebellar ataxia, spinal muscular atrophy, Steele-Richardson, Olszewski disease, and tabes dorsalis.
  • neurological and psychiatric diseases that may be treated with the compounds of the invention include Tourette's syndrome and obsessive compulsive disorder.
  • the compounds of the invention may be used to reduce the body temperature of a subject. Because reduction in body temperature has been shown to be beneficial in subjects who who are in need of neuroprotection, e.g., may be suffering from, or may have recently suffered from, a stroke, cerebral ischemia, cardiac ischemia, or a nerve injury such as a spinal chord injury or head or brain injury (e.g., traumatic brain injury), such a treatment would therefore be useful in reducing complications of these conditions. Reduction of body temperature may also be desired during surgical procedures such as cardiac surgery (e.g., open heart surgery) or other major surgery or where the subject is suffering from malignant hypothermia.
  • cardiac surgery e.g., open heart surgery
  • other major surgery where the subject is suffering from malignant hypothermia.
  • Pain Neurotensin is also known to have analgesic effects.
  • the compounds of the invention may be used to reduce pain in a subject.
  • the subject may be suffering from an acute pain (e.g., selected from the group consisting of mechanical pain, heat pain, cold pain, ischemic pain, and chemical-induced pain).
  • pain include peripheral or central neuropathic pain, inflammatory pain, migraine-related pain, headache-related pain, irritable bowel syndrome-related pain, fibromyalgia- related pain, arthritic pain, skeletal pain, joint pain, gastrointestinal pain, muscle pain, angina pain, facial pain, pelvic pain, claudication, postoperative pain, post traumatic pain, tension-type headache, obstetric pain, gynecological pain, or chemotherapy- induced pain.
  • ATTORNEY DOCKET NO. V82774W0 invention may be used to treat such disorders.
  • the metabolic disorder may be diabetes (e.g., Type I or Type II), obesity, diabetes as a consequence of obesity, hyperglycemia, dyslipidemia, hypertriglyceridemia, syndrome X, insulin resistance, impaired glucose tolerance (IGT), diabetic dyslipidemia, hyperlipidemia, a cardiovascular disease, or hypertension.
  • the subject may be overweight, obese, or bulimic.
  • Neurotensin has also been suggested to be able to treat drug addiction or reduce drug abuse in subjects, particularly with psychostimulants.
  • the compounds of the invention may be useful in treating addiction to or abuse of drugs such as amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine, nicotine, cocaine, methylphenidate, and arecoline.
  • NT may also be used to treat alcohol addiction.
  • the present invention also features pharmaceutical compositions that contain a therapeutically effective amount of a compound of the invention.
  • the composition can be formulated for use in a variety of drug delivery systems.
  • One or more physiologically acceptable excipients or carriers can also be included in the composition for proper formulation.
  • Suitable formulations for use in the present invention are found in Remington 's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 17th ed., 1985.
  • Langer Science 249: 1527-1533, 1990.
  • the pharmaceutical compositions are intended for parenteral, intranasal, topical, oral, or local administration, such as by a transdermal means, for prophylactic and/or therapeutic treatment.
  • compositions can be administered parenterally (e.g., by intravenous, intramuscular, or subcutaneous injection), or by oral ingestion, or by topical application or intraarticular injection at areas affected by the vascular or cancer condition.
  • Additional routes of administration include intravascular, intra-arterial, intratumor, intraperitoneal, intraventricular, intraepidural, as well as nasal, ophthalmic, intrascleral, intraorbital, rectal, topical, or aerosol inhalation administration.
  • Sustained release administration is also specifically PATENT
  • compositions for parenteral administration that comprise the above mention agents dissolved or suspended in an acceptable carrier, preferably an aqueous carrier, e.g., water, buffered water, saline, PBS, and the like.
  • an acceptable carrier preferably an aqueous carrier
  • the compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, wetting agents, detergents and the like.
  • the invention also provides compositions for oral delivery, which may contain inert ingredients such as binders or fillers for the formulation of a tablet, a capsule, and the like.
  • compositions for local administration which may contain inert ingredients such as solvents or emulsif ⁇ ers for the formulation of a cream, an ointment, and the like.
  • compositions may be sterilized by conventional sterilization techniques, or may be sterile filtered.
  • the resulting aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • the pH of the preparations typically will be between 3 and 1 1 , more preferably between 5 and 9 or between 6 and 8, and most preferably between 7 and 8, such as 7 to 7.5.
  • the resulting compositions in solid form may be packaged in multiple single dose units, each containing a fixed amount of the above- mentioned agent or agents, such as in a sealed package of tablets or capsules.
  • the composition in solid form can also be packaged in a container for a flexible quantity, such as in a squeezable tube designed for a topically applicable cream or ointment.
  • compositions containing an effective amount can be administered for prophylactic or therapeutic treatments.
  • compositions can be administered to a subject with a clinically determined predisposition or increased susceptibility to a metabolic disorder or neurological disease.
  • Compositions of the invention can be administered to the subject (e.g., a human) in an amount sufficient to delay, reduce, or preferably prevent the onset of clinical disease.
  • compositions are administered to a subject (e.g., a human) already suffering from disease (e.g., a metabolic disorder such as those described herein, or a neurological disease) in an amount sufficient to cure or at least partially arrest the symptoms of the condition and its complications.
  • An amount adequate to accomplish this purpose is defined as a "therapeutically effective amount," an amount of a PATENT
  • ATTORNEY DOCKET NO. V82774W0 compound sufficient to substantially improve some symptom associated with a disease or a medical condition.
  • a metabolic disorder e.g., those described herein
  • an agent or compound which decreases, prevents, delays, suppresses, or arrests any symptom of the disease or condition would be therapeutically effective.
  • a therapeutically effective amount of an agent or compound is not required to cure a disease or condition but will provide a treatment for a disease or condition such that the onset of the disease or condition is delayed, hindered, or prevented, or the disease or condition symptoms are ameliorated, or the term of the disease or condition is changed or, for example, is less severe or recovery is accelerated in an individual.
  • Amounts effective for this use may depend on the severity of the disease or condition and the weight and general state of the subject, but generally range from about 0.05 ⁇ g to about 1000 ⁇ g (e.g., 0.5-100 ⁇ g) of an equivalent amount of exendin- 4 the agent or agents per dose per subject.
  • Suitable regimes for initial administration and booster administrations are typified by an initial administration followed by repeated doses at one or more hourly, daily, weekly, or monthly intervals by a subsequent administration.
  • the total effective amount of an agent present in the compositions of the invention can be administered to a mammal as a single dose, either as a bolus or by infusion over a relatively short period of time, or can be administered using a fractionated treatment protocol, in which multiple doses are administered over a more prolonged period of time (e.g., a dose every 4-6, 8-12, 14- 16, or 18-24 hours, or every 2-4 days, 1-2 weeks, once a month).
  • a fractionated treatment protocol in which multiple doses are administered over a more prolonged period of time (e.g., a dose every 4-6, 8-12, 14- 16, or 18-24 hours, or every 2-4 days, 1-2 weeks, once a month).
  • continuous intravenous infusion sufficient to maintain therapeutically effective concentrations in the blood are contemplated.
  • the therapeutically effective amount of one or more agents present within the compositions of the invention and used in the methods of this invention applied to mammals can be determined by the ordinarily-skilled artisan with consideration of individual differences in age, weight, and the condition of the mammal. Because certain compounds of the invention exhibit an enhanced ability to cross the BBB, the dosage of the compounds of the invention can be lower than (e.g., less than or equal to about 90%, 75%, 50%, 40%, 30%, 20%, 15%, 12%, 10%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% of) the equivalent dose of required for a therapeutic effect of the unconjugated agonist.
  • the agents of the invention are PATENT
  • ATTORNEY DOCKET NO. V82774W0 administered to a subject (e.g. a mammal, such as a human) in an effective amount, which is an amount that produces a desirable result in a treated subject (e.g. reduction in glycemia, reduced weight gain, increased weight loss, and reduced food intake).
  • an effective amount which is an amount that produces a desirable result in a treated subject (e.g. reduction in glycemia, reduced weight gain, increased weight loss, and reduced food intake).
  • Therapeutically effective amounts can also be determined empirically by those of skill in the art.
  • the subject may also receive an agent in the range of about 0.05 to 10,000 ⁇ g equivalent dose as compared to neurotensin per dose one or more times per week (e.g., 2, 3, 4, 5, 6, or 7 or more times per week), 0.1 to 2,500 (e.g., 2,000, 1,500, 1,000, 500, 100, 10, 1, 0.5, or 0.1) ⁇ g dose per day or week.
  • a subject may also receive an agent of the composition in the range of 0.1 to 3,000 ⁇ g per dose once every two or three weeks.
  • compositions of the invention comprising an effective amount can be carried out with dose levels and pattern being selected by the treating physician.
  • the dose and administration schedule can be determined and adjusted based on the severity of the disease or condition in the subject, which may be monitored throughout the course of treatment according to the methods commonly practiced by clinicians or those described herein.
  • the compounds of the present invention may be used in combination with either conventional methods of treatment or therapy or may be used separately from conventional methods of treatment or therapy.
  • compositions according to the present invention may be comprised of a combination of a compound of the present invention in association with a pharmaceutically acceptable excipient, as described herein, and another therapeutic or prophylactic agent known in the art.
  • Example 1 Synthesis of a neurotensin- Angiopep-2 conjugate An exemplary neurotensin-Angiopep-2 conjugate was synthesized using the scheme described below. As used in these examples, the abbreviation NT refers to the pE-substituted neurotensin peptide described below. PATENT
  • Neurotensin peptide synthesis pELYENKPRRPYIL-OH where the unusual amino acid L-pyroglutamic acid (pE) is used, was synthesized using SPPS (Solid phase peptide synthesis). SPPS was carried out on a Protein Technologies, Inc. Symphony® peptide synthesizer using Fmoc (9-fluorenylmethyloxycarbonyl) amino-terminus protection. The peptide was synthesized on a 100 ⁇ mol scale using a 5-fold excess of Fmoc-amino acids (200 mM) relative to the resin.
  • SPPS Solid phase peptide synthesis
  • Coupling was performed by a pre-loaded Fmoc-Leu-Wang resin (0.48 mmol/g) for carboxyl-terminus acids using 1 : 1 :2 amino acid/activator/NMM in DMF with HBTU (2-(lH-benzotriazol-l-yl)-l,l,3,3- tetramethyluronium hexafluorophosphate) and NMM (N-methylmorpholine). Deprotection was carried out using 20% piperidine/DMF. The resin-bound product was routinely cleaved using a solution comprised of TFA/water/TES: 95/2.5/2.5 for 2 hours at room temperature.
  • Pre-loaded Fmoc-Leu-Wang resin (0.48 mmol/g) was purchased from ChemPep, Fmoc-amino acids, HBTU from Chemlmpex, and the unusual L- pyroglutamic acid from Sigma-Aldrich.
  • Side protecting groups for amino acids were Trt (trityl) for aspargine, tBu (ter-butyl) for glutamic acid and tyrosine, Pbf (pentamethyldihydrobenzofuran-5-sulfonyl) for arginine, and tBoc (tButyloxycarbonyl) for lysine.
  • N-lysine primary amine of NT was activated by treating a solution of NT
  • NT-AN2Cys-NH2 Conjugation was performed with the maleimido-containing EMCS-NT and the free thiol residue of AN2Cys-NH 2 .
  • the pH of the solution of EMCS-NT was adjusted from 1.65 to 6.42 by a slow addition of a 0.1N NaOH solution.
  • a solution of AN2Cys-NH 2 (46.4 mg, 14.9 ⁇ mol, 1 eq. in 2.5 ml of PBS 4x, pH 7.64) was added to the solution of EMCS-NT.
  • ATTORNEY DOCKET NO. V82774WO in Figure 4 Purification of NT-AN2Cys-NH2 was performed using a column (GE Healthcare) containing 30 RPC resin (Polystyrene/divinyl benzene), 30 ml, Sample was loaded in the amount of 74 mg in 4 ml reaction buffer (10 % ACN in H 2 O, 0.05% TFA (200 ul)). Solution A was H 2 O, 0.05 % TFA, and Solution B was ACN, 0.05 % TFA. The flow rate was 5-9 ml/min, using a gradient of 10% to 25% of Solution B.
  • the conjugated NT- AN2Cys-NH 2 was obtained as a pure white solid (5.5 mg, 9% over 2 steps, purity >95%).
  • the mass was confirmed by ESI-TOF MS (Bruker Daltonics); MW was calculated to be 4270.76 and was found to be 4269.17 (m/z 712.54 (+6), 854.84 (+5), 1068.29 (+4), 1424.04 (+3)).
  • the conjugate was stored under nitrogen atmosphere, below -20 0 C.
  • ATTORNEY DOCKET NO. V82774WO dose (5 mg/kg) of NT-An2 caused a stronger decrease in body temperature indicating that the effect of NT-An2 is dose dependent.
  • mice In a first experiment, mice first received an intravenous 5 mg/kg bolus injection of NT-An2, followed by an intravenous infusion (10 mg/kg/hr) 1 hour later for a duration of 2.5 hours. The body temperature continued to decrease during the infusion, reaching a nadir of -1 1 0 C ( Figure 10). After the end of the infusion, body temperature slowly returned to 37 0 C, and the animals recovered.
  • mice We also tested the ability of NT-An2 to induce analgesia in mice.
  • NT(8-13) RRPYIL
  • Ac-LysNT(8-13) Ac-Lys-[D-Tyr”]NT(8-13)
  • pGlu- LysNT(8-13) pGlu- LysNT(8-13)
  • MHA-NT(8-13) MHA-NT(8-13)
  • ⁇ -mercaptoMHA-NT(8-13) see below.
  • NT and the NT(8-13) analogs were synthesized by using a SPPS method on a Protein Technologies, Inc. Symphony ® peptide synthesizer and Fmoc chemistry.
  • Pre- loaded Fmoc-Leu-Wang resin (0.48 mmol/g) was purchased from ChemPep, Fmoc- PATENT
  • ATTORNEY DOCKET NO. V82774WO amino acids HBTU from Chemlmpex, the unusual pE from Sigma-Aldrich, unnatural D-Tyrosine from Chemlmpex, Sulfo-EMCS from Pierce Biotechnology. Side protecting groups for amino acids were Trt for aspargine, tBu for glutamic acid and tyrosine, Pbf for arginine, and tBoc for lysine. Mass was confirmed by ESI-TOF MS (MicroTof, Bruker Daltonics).
  • NT neurotensin
  • the crude peptide was precipitated using ice-cold ether and was purified by RP-HPLC chromatography, Waters Delta Prep 4000, Kromasil 100- 10-C 18,
  • MHA-NT(8- 13) MHA-RRPYIL-OH
  • NT MHA-RRPYIL-OH
  • Sulfo-EMCS 1.2 eq. in DMF
  • the crude peptide was purified by RP-HPLC chromatography, Waters Delta Prep 4000, Waters BEH Phenyl, H 2 CVACN with 0.05%TFA ("Method B"). This generated 55 mg of product, 73 % yield, purity HPLC >95 %, calc. 1010.19, found 1010.59, m/z 505.81 (+2).
  • ANG-Cys-NH2 was synthesized using a 5-fold excess of Fmoc-AA (200 mM) relative to the resin.
  • G 6 S 7 is coupled as the pseudoproline dipeptide GS.
  • Coupling was performed from a Rink amide MBHA resin with NIe (0.40 mmol/g) for carboxyl- terminus amides using 1 :1 :4 AA/HCTU/NMM in DMF.
  • Cleavage of the resin-bound product was carried out using TFA/water/EDT/TES: 94/2.5/2.5/1 for 2 h at room temperature.
  • the crude peptide was precipitated using ice-cold ether, and purified by RP- HPLC chromatography twice successively, Waters Delta Prep 4000, Kromasil 100- 10-Cl 8 and Waters BEH Phenyl, H 2 O/ACN with 0.05%TFA ("Method C"). Acetonitrile was evaporated from the collected fractions and lyophilized. This resulted in formation of a white and fluffy solid, 565 mg, 28 % yield, purity HPLC >90 %, calc. 2403.63; found 2402.05, m/z 1202.53 (+2), 802.04 (+3), 601.78 (+4).
  • Example 6 Characterization of neurotensin analogs To determine which NT analog or analogs would be best suited for conjugation to Angiopep-2, we evaluated the ability of each analog to induce hypothermia in mice. Bolus intravenous injections of 7.5 mg/kg of NT(8-13), Ac- PATENT
  • Lys-NT(8-13), Ac-Lys-[D-Tyr"]NT(8-13), pGlu-NT(8-13), and a control were performed (Figure 16) and body temperature was measured over a period of 120 minutes.
  • Ac-Lys-[D-Tyr n ]NT(8-13) exhibited the greatest reduction in body temperature of the analogs tested. This analog was therefore selected for conjugation and further experimentation.
  • NT-AN2 Three neurotensin and NT analog conjugates were generated, NT-AN2 (as described above), NT(8- 13)-AN2, and Ac-Lys-[D-Tyr' ']NT(8- 13)-AN2. The structure of each of these conjugates is shown in the table below.
  • conjugates analogs were synthesized by using a SPPS method on a Protein Technologies, Inc. Symphony ® peptide synthesizer and Fmoc chemistry.
  • Preloaded Fmoc-Leu-Wang resin (0.48 mmol/g) was purchased from ChemPep, Fmoc- amino acids, HBTU from Chemlmpex, the unusual pE from Sigma-Aldrich, unnatural PATENT
  • the conjugated ANG-NT was obtained as a pure white solid, 412 mg, 65% yield, 54 % over 2 steps, purity HPLC >95 %, calc. 4270.76, found 4269.17, m/z 712.54 (+6), 854.84 (+5), 1068.29 (+4), 1424.04 (+3).
  • a bolus of a control, unconjugated NT, NT-An2, NT(8-13)-An2, and Ac-LyS-[D- Tyr ⁇ ]NT(8-13)-An2 were each injected intravenously into mice, and body temperature was monitored over a period of 120 minutes. Little difference between the control and the unconjugated NT, some effect was observed with the NT(8-13)- An2 conjugate, and a larger effect was observed with both the NT-An2 and Ac-Lys- [D-Tyr n ]NT(8-13)-An2 conjugates (Figure 17).
  • ATTORNEY DOCKET NO. V82774WO results are presented in the table below.
  • the different results for NT and ANG-NT i.e., NT-An2 represent results from different production batches of each compound.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Addiction (AREA)
  • Molecular Biology (AREA)
  • Neurology (AREA)
  • Diabetes (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Psychiatry (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Epidemiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Rheumatology (AREA)
  • Dermatology (AREA)
  • Emergency Medicine (AREA)
  • Child & Adolescent Psychology (AREA)
  • Endocrinology (AREA)
  • Pain & Pain Management (AREA)
  • Anesthesiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP09829934.0A 2008-12-05 2009-12-07 Neurotensin konjugat und seine verwendungen Not-in-force EP2370471B1 (de)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US20094708P 2008-12-05 2008-12-05
US18114409P 2009-05-26 2009-05-26
US22548609P 2009-07-14 2009-07-14
PCT/CA2009/001779 WO2010063122A1 (en) 2008-12-05 2009-12-07 Conjugates of neurotensin or neurotensin analogs and uses thereof

Publications (3)

Publication Number Publication Date
EP2370471A1 true EP2370471A1 (de) 2011-10-05
EP2370471A4 EP2370471A4 (de) 2013-05-01
EP2370471B1 EP2370471B1 (de) 2017-02-22

Family

ID=42232846

Family Applications (1)

Application Number Title Priority Date Filing Date
EP09829934.0A Not-in-force EP2370471B1 (de) 2008-12-05 2009-12-07 Neurotensin konjugat und seine verwendungen

Country Status (10)

Country Link
US (1) US9914754B2 (de)
EP (1) EP2370471B1 (de)
JP (2) JP5759379B2 (de)
CN (1) CN102307904A (de)
AU (1) AU2009322043A1 (de)
BR (1) BRPI0922689A2 (de)
CA (1) CA2745524C (de)
MX (1) MX2011005963A (de)
WO (1) WO2010063122A1 (de)
ZA (1) ZA201104495B (de)

Families Citing this family (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4903036B2 (ja) * 2003-01-06 2012-03-21 アンジオケム・インコーポレーテッド 血液脳関門を通過する担体としてのアプロチニンおよび類似体
US20090016959A1 (en) * 2005-02-18 2009-01-15 Richard Beliveau Delivery of antibodies to the central nervous system
DK2360258T3 (en) 2005-02-18 2015-01-12 Angiochem Inc Aprotininpolypeptider to transport a compound of blood-brain-barrier
EP1907009A4 (de) 2005-07-15 2009-09-02 Angiochem Inc Verwendung von aprotinin-polypeptiden als träger in pharmazeutischen konjugaten
CA2666841A1 (en) 2006-10-19 2008-04-24 Angiochem, Inc. Compounds for stimulating p-glycoprotein function and uses thereof
US9365634B2 (en) 2007-05-29 2016-06-14 Angiochem Inc. Aprotinin-like polypeptides for delivering agents conjugated thereto to tissues
DK2279008T3 (en) * 2008-04-18 2019-04-29 Angiochem Inc PHARMACEUTICAL COMPOSITIONS OF PACLITAXEL, PACLITAXEL ANALOGS OR PACLITAXEL CONJUGATES AND RELATED PROCEDURES FOR PREPARATION AND USE
CN102245642A (zh) 2008-10-15 2011-11-16 安吉奥开米公司 Glp-1激动剂的结合物及其用途
RU2531591C2 (ru) 2008-10-15 2014-10-20 Ангиокем Инк. Конъюгаты этопозида и доксорубицина для доставки лекарственных средств
AU2009322043A1 (en) 2008-12-05 2011-07-07 Angiochem Inc. Conjugates of neurotensin or neurotensin analogs and uses thereof
BRPI0922611A2 (pt) 2008-12-17 2018-11-06 Angiochem Inc inibidores de metaloproteína de matriz de membrana tipo 1 e usos dos mesmos
CA2759129C (en) 2009-04-20 2018-12-11 Angiochem Inc. Treatment of ovarian cancer using an anticancer agent conjugated to an angiopep-2 analog
US9161988B2 (en) 2009-07-02 2015-10-20 Angiochem Inc. Multimeric peptide conjugates and uses thereof
CN103080125A (zh) * 2010-07-02 2013-05-01 安吉奥开米公司 用于治疗性结合物的短且含d氨基酸的多肽及其使用
BR112014013250A2 (pt) * 2011-12-01 2019-09-24 Angiochem Inc compostos com enzima alvo e usos dos mesmos
US20150037311A1 (en) * 2011-12-01 2015-02-05 Angiochem Inc. Targeted lysosomal enzyme compounds
CN103308670B (zh) * 2012-03-08 2017-06-09 思芬构技术有限公司 用于预测对象患糖尿病和/或代谢综合征的风险的方法
CN104662151A (zh) * 2012-06-15 2015-05-27 安吉奥开米公司 靶向的艾杜糖醛酸酶化合物
EP2885318A4 (de) 2012-08-14 2016-03-30 Angiochem Inc Peptid-dendrimer-konjugate und ihre verwendungen
JP2015536658A (ja) * 2012-11-30 2015-12-24 アンジオケム インコーポレーテッド 標的化イズロン酸−２−スルファターゼ化合物
EP2740726A1 (de) 2012-12-07 2014-06-11 3B Pharmaceuticals GmbH Neurotensin-Rezeptorligande
US10450343B2 (en) 2013-03-21 2019-10-22 Sanofi-Aventis Deutschland Gmbh Synthesis of cyclic imide containing peptide products
HUE034308T2 (en) 2013-03-21 2018-02-28 Sanofi Aventis Deutschland Preparation of hydantoin-containing peptide products
WO2014194427A1 (en) * 2013-06-06 2014-12-11 Angiochem Inc. Targeted iduronate-2-sulfatase fusion proteins
WO2014194428A1 (en) * 2013-06-06 2014-12-11 Angiochem Inc. Targeted heparan sulfatase compounds
US20160367691A1 (en) * 2013-06-06 2016-12-22 Angiochem Inc. Targeted enzyme compounds and uses thereof
EP2896402A1 (de) 2014-01-20 2015-07-22 Vect-Horus Aktivierte Neurotensinmoleküle und Verwendungen dafür
RU2743781C2 (ru) * 2014-06-10 2021-02-25 3Б Фармасьютикалз Гмбх Конъюгат, содержащий лиганд рецепторов нейротензина, и его применение
EP2954933A1 (de) 2014-06-10 2015-12-16 3B Pharmaceuticals GmbH Konjugat mit einem Neurotensinrezptorligand
EP2954934A1 (de) 2014-06-11 2015-12-16 3B Pharmaceuticals GmbH Konjugat aus einem Neurotensinrezeptorliganden und Verwendung davon
DK3307326T3 (da) 2015-06-15 2020-10-19 Angiochem Inc Fremgangsmåder til behandling af leptomeningeal karcinomatose
JP6630426B2 (ja) 2015-07-06 2020-01-15 ユーシービー バイオファルマ エスピーアールエル Ｔａｕ結合抗体
ES2882634T3 (es) * 2015-11-24 2021-12-02 Transfert Plus Sec Compuestos peptídicos y conjugados con péptidos para el tratamiento del cáncer mediante quimioterapia mediada por receptores
US10473670B2 (en) 2016-02-25 2019-11-12 University Of Kentucky Research Foundation Method of predicting obesity comprising measuring neurotensin
WO2017180834A1 (en) * 2016-04-13 2017-10-19 Tarveda Therapeutics, Inc. Neurotensin receptor binding conjugates and formulations thereof
CA3119793A1 (en) 2017-11-28 2019-08-01 Board Of Regents Of The University Of Nebraska Radiopharmaceuticals and methods of use thereof
WO2021078833A1 (en) * 2019-10-22 2021-04-29 Genethon Chimeric polypeptides and uses thereof
WO2023247754A1 (en) * 2022-06-23 2023-12-28 Draupnir Bio Aps Bifunctional molecules that selectively induce degradation of extracellular targets in lysosomes

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040162284A1 (en) * 2003-02-19 2004-08-19 Harris Herbert W. Method of lowering body temperature with (S) tofisopam
WO2006086870A1 (en) * 2005-02-18 2006-08-24 Angiochem Inc. Aprotinin polypeptides for transporting a compound across the blood-brain barrier

Family Cites Families (199)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4671958A (en) 1982-03-09 1987-06-09 Cytogen Corporation Antibody conjugates for the delivery of compounds to target sites
CA1307736C (en) 1986-03-13 1992-09-22 David Mark Robertson Method of assay of inhibin
US4902505A (en) 1986-07-30 1990-02-20 Alkermes Chimeric peptides for neuropeptide delivery through the blood-brain barrier
US4801575A (en) 1986-07-30 1989-01-31 The Regents Of The University Of California Chimeric peptides for neuropeptide delivery through the blood-brain barrier
US4904768A (en) 1987-08-04 1990-02-27 Bristol-Myers Company Epipodophyllotoxin glucoside 4'-phosphate derivatives
GB2208511A (en) 1987-08-07 1989-04-05 Bayer Ag Variants of bovine pancreatic trypsin inhibitor produced by recombinant dna technology
US4942184A (en) 1988-03-07 1990-07-17 The United States Of America As Represented By The Department Of Health And Human Services Water soluble, antineoplastic derivatives of taxol
US5632990A (en) 1988-04-22 1997-05-27 Cancer Research Campaign Tech. Ltd. Treatment for tumors comprising conjugated antibody A5B7 and a prodrug
US5258499A (en) 1988-05-16 1993-11-02 Vestar, Inc. Liposome targeting using receptor specific ligands
US5028697A (en) 1988-08-08 1991-07-02 Eli Lilly And Company Cytotoxic antibody conjugates of hydrazide derivatized methotrexate analogs via simple organic linkers
US5169933A (en) 1988-08-15 1992-12-08 Neorx Corporation Covalently-linked complexes and methods for enhanced cytotoxicity and imaging
US5223409A (en) 1988-09-02 1993-06-29 Protein Engineering Corp. Directed evolution of novel binding proteins
US5948634A (en) 1988-12-21 1999-09-07 The General Hospital Coporation Neural thread protein gene expression and detection of alzheimer's disease
DE3912638A1 (de) 1989-04-18 1990-10-31 Bayer Ag Gentechnologisch hergestellte homologe des alzheimer protease inhibitors, wirtstaemme sowie expressionsvektoren fuer ihre herstellung und ihre verwendung als arzneimittel
US5126249A (en) 1989-05-09 1992-06-30 Eli Lilly And Company Enzymatic removal of a protein amino-terminal sequence
US6020145A (en) 1989-06-30 2000-02-01 Bristol-Myers Squibb Company Methods for determining the presence of carcinoma using the antigen binding region of monoclonal antibody BR96
US6475781B1 (en) 1990-05-17 2002-11-05 Dana-Farber Cancer Institute, Inc. Trans-dominant suppressor genes for oligomeric proteins
US5714167A (en) 1992-06-15 1998-02-03 Emisphere Technologies, Inc. Active agent transport systems
GB9017008D0 (en) 1990-08-02 1990-09-19 Erba Carlo Spa Process for the enzymatic preparation of basic fibroblast growth factor
US5525491A (en) 1991-02-27 1996-06-11 Creative Biomolecules, Inc. Serine-rich peptide linkers
US6495513B1 (en) 1991-03-11 2002-12-17 Curis, Inc. Morphogen-enhanced survival and repair of neural cells
US5955444A (en) 1991-08-09 1999-09-21 Massachusetts Institute Of Technology Method of inhibiting abnormal tau hyper phosphorylation in a cell
US5908832A (en) * 1991-10-07 1999-06-01 University Of Houston - Clearlake Peptide analog
US5627270A (en) 1991-12-13 1997-05-06 Trustees Of Princeton University Glycosylated steroid derivatives for transport across biological membranes and process for making and using same
US5204354A (en) * 1992-02-14 1993-04-20 Merck & Co., Inc. Substituted quinazolinones as neurotensin antagonists useful in the treatment of CNS disorders
GB9213077D0 (en) 1992-06-19 1992-08-05 Erba Carlo Spa Polymerbound taxol derivatives
EP0671944A4 (de) 1992-09-25 1996-07-24 Corvas Int Inc Inhibitoren des faktor viia-gewebsfaktorrkomplex abegeleitet vom pankreatischerinder-trypsininhibitor.
EP0599303A3 (de) 1992-11-27 1998-07-29 Takeda Chemical Industries, Ltd. Peptide-Konjugate
WO1994019692A1 (en) 1993-02-18 1994-09-01 The General Hospital Corporation Alzheimer's disease therapeutics
US6974578B1 (en) * 1993-12-28 2005-12-13 Allergan, Inc. Method for treating secretions and glands using botulinum toxin
EP0820466A2 (de) 1995-04-04 1998-01-28 Advanced Bioconcept Inc. Fluoreszierende peptide
AU5854096A (en) 1995-05-08 1996-11-29 Scios Inc. Kunitz type protease inhibitors
ZA963619B (en) 1995-05-08 1996-11-22 Scios Inc Protease inhibitor peptides
AU5908296A (en) 1995-05-31 1996-12-24 Fred Hutchinson Cancer Research Center Compositions and methods for targeted delivery of effector m olecules
US5780265A (en) 1995-06-05 1998-07-14 Genentech, Inc. Kunitz type plasma kallikrein inhibitors
US5665702A (en) 1995-06-06 1997-09-09 Biomeasure Incorporated Ionic molecular conjugates of N-acylated derivatives of poly(2-amino-2-deoxy-D-glucose) and polypeptides
AU6267896A (en) 1995-06-07 1996-12-30 Imclone Systems Incorporated Antibody and antibody fragments for inhibiting the growth oftumors
HU226419B1 (en) 1996-03-11 2008-12-29 Aerovance Human bikunin
WO1997040854A2 (en) 1996-05-01 1997-11-06 Antivirals Inc. Polypeptide conjugates for transporting substances across cell membranes
HU227021B1 (en) 1996-08-30 2010-05-28 Novo Nordisk As Glp-1 derivatives
DE19636889A1 (de) 1996-09-11 1998-03-12 Felix Dr Kratz Antineoplastisch wirkende Transferrin- und Albuminkonjugate zytostatischer Verbindungen aus der Gruppe der Anthrazykline, Alkylantien, Antimetabolite und Cisplatin-Analoga und diese enthaltende Arzneimittel
WO1998016201A1 (en) 1996-10-11 1998-04-23 Sequus Pharmaceuticals, Inc. Therapeutic liposome composition and method
US6056973A (en) 1996-10-11 2000-05-02 Sequus Pharmaceuticals, Inc. Therapeutic liposome composition and method of preparation
US5948750A (en) 1996-10-30 1999-09-07 Merck & Co., Inc. Conjugates useful in the treatment of prostate cancer
AU6682598A (en) 1997-03-04 1998-09-22 Bio-Technology General Corporation Isolation of tissue specific peptide ligands and their use for targeting pharmaceuticals to organs
US6126965A (en) 1997-03-21 2000-10-03 Georgetown University School Of Medicine Liposomes containing oligonucleotides
GB9705903D0 (en) 1997-03-21 1997-05-07 Elliott Gillian D VP22 Proteins and uses thereof
EP0975370B9 (de) 1997-05-21 2004-11-03 The Board Of Trustees Of The Leland Stanford Junior University Zusammensetzung und verfahren zur verzögerung des transports durch biologische membranen
US6391305B1 (en) 1997-09-10 2002-05-21 Merck & Co., Inc. Conjugates useful in the treatment of prostate cancer
US6093692A (en) 1997-09-25 2000-07-25 The University Of Southern California Method and compositions for lipidization of hydrophilic molecules
US6475481B2 (en) 1997-11-18 2002-11-05 Canji Inc Purging of stem cell products
WO1999026657A1 (en) 1997-11-25 1999-06-03 Musc Foundation For Research Development Inhibitors of nitric oxide synthase
US5981564A (en) 1998-07-01 1999-11-09 Universite Laval Water-soluble derivatives of paclitaxel, method for producing same and uses thereof
GB9814527D0 (en) 1998-07-03 1998-09-02 Cyclacel Ltd Delivery system
US6703381B1 (en) 1998-08-14 2004-03-09 Nobex Corporation Methods for delivery therapeutic compounds across the blood-brain barrier
US5922754A (en) 1998-10-02 1999-07-13 Abbott Laboratories Pharmaceutical compositions containing paclitaxel
AU768027B2 (en) 1999-02-24 2003-11-27 Uab Research Foundation, The Taxane derivatives for targeted therapy of cancer
US6924264B1 (en) 1999-04-30 2005-08-02 Amylin Pharmaceuticals, Inc. Modified exendins and exendin agonists
EP1180121B9 (de) 1999-05-17 2004-09-08 Conjuchem, Inc. Lang wirkende insulinotrope peptide
GB9911683D0 (en) 1999-05-19 1999-07-21 Chiron Spa Antigenic peptides
US6180607B1 (en) 1999-08-05 2001-01-30 Christopher Davies Protein having proteinase inhibitor activity
US6713454B1 (en) 1999-09-13 2004-03-30 Nobex Corporation Prodrugs of etoposide and etoposide analogs
CA2385882C (en) 1999-09-24 2009-11-24 Genentech, Inc. Tyrosine derivatives
US6136846A (en) 1999-10-25 2000-10-24 Supergen, Inc. Formulation for paclitaxel
DE19953696A1 (de) 1999-11-09 2001-05-10 Alexander Cherkasky Selektive proteolytische Synzyme (SPS)
IL142707A0 (en) 2000-04-27 2002-03-10 Pfizer Prod Inc Methods of treating obesity using a neurotensin receptor ligand
CA2417136A1 (en) * 2000-09-01 2002-03-07 The Governing Council Of The University Of Toronto Proteins related to schizophrenia and uses thereof
CA2355334A1 (en) 2000-10-16 2002-04-16 Procyon Biopharma Inc. Pharmaceutical preparations and methods for inhibiting tumors
US6919370B2 (en) 2000-11-28 2005-07-19 Transform Pharmaceuticals, Inc. Pharmaceutical formulations comprising paclitaxel, derivatives, and pharmaceutically acceptable salts thereof
JP2004528014A (ja) 2000-12-07 2004-09-16 イーライ・リリー・アンド・カンパニー Ｇｌｐ−１融合タンパク質
CA2441484A1 (en) 2001-03-23 2002-10-03 Napro Biotherapeutics, Inc. Molecular conjugates for use in treatment of cancer
IL158419A0 (en) 2001-04-19 2004-05-12 Scripps Research Inst Methods and composition for the production of orthoganal trna-aminoacyl trna synthetase pairs
US20030170891A1 (en) 2001-06-06 2003-09-11 Mcswiggen James A. RNA interference mediated inhibition of epidermal growth factor receptor gene expression using short interfering nucleic acid (siNA)
ATE445838T1 (de) 2001-07-25 2009-10-15 Raptor Pharmaceutical Inc Zusammensetzungen und verfahren zur modulation des transports durch die blut-hirn-schranke
US20040161776A1 (en) 2001-10-23 2004-08-19 Maddon Paul J. PSMA formulations and uses thereof
US7192921B2 (en) 2001-11-08 2007-03-20 The Burnham Institute Peptides that home to tumor lymphatic vasculature and methods of using same
WO2003066859A2 (en) 2002-02-07 2003-08-14 Yissum Research Development Company Of The Hebrew University Of Jerusalem Amino acid sequences capable of facilitating penetration across a biological barrier
JP4188909B2 (ja) 2002-03-29 2008-12-03 クレアゼン インコーポレーテッド 細胞質残留性細胞膜透過ペプチド及びこれの用途｛ＣｙｔｏｐｌａｓｍｉｃＴｒａｎｓｄｕｃｔｉｏｎＰｅｐｔｉｄｅｓａｎｄＵｓｅｓｔｈｅｒｅｏｆ｝
US6881829B2 (en) 2002-04-26 2005-04-19 Chimeracom, L.L.C. Chimeric hybrid analgesics
CA2487815A1 (en) 2002-05-29 2003-12-11 Symbiontics, Inc. Targeted therapeutic proteins
JP2005537244A (ja) 2002-06-28 2005-12-08 ナステック・ファーマシューティカル・カンパニー・インコーポレーテッド 療法化合物の粘膜搬送を増進させるための、上皮接合部接着分子の生理機能を調節する組成物および方法
AU2003295600A1 (en) 2002-11-14 2004-06-15 Dharmacon, Inc. Functional and hyperfunctional sirna
US7829694B2 (en) 2002-11-26 2010-11-09 Medtronic, Inc. Treatment of neurodegenerative disease through intracranial delivery of siRNA
US7388079B2 (en) 2002-11-27 2008-06-17 The Regents Of The University Of California Delivery of pharmaceutical agents via the human insulin receptor
US20040102369A1 (en) 2002-11-27 2004-05-27 The Regents Of The University Of California Transport of basic fibroblast growth factor across the blood brain barrier
US7319090B2 (en) 2002-11-27 2008-01-15 University Of North Carolina At Chapel Hill Methods of treating cerebral ischemia
JP4903036B2 (ja) 2003-01-06 2012-03-21 アンジオケム・インコーポレーテッド 血液脳関門を通過する担体としてのアプロチニンおよび類似体
EP1615655B1 (de) 2003-04-08 2012-02-22 Biotempt B.V. Verwendung von hcg-fragmente enthaltene zusammensetzungen zur mukosalen und oralen anwendung
PT1615646E (pt) 2003-04-08 2015-02-12 Progenics Pharm Inc Formulações farmacêuticas com metilnaltrexona
EP2666858A1 (de) 2003-04-17 2013-11-27 Alnylam Pharmaceuticals Inc. Modifizierte iRNA-Wirkstoffe
WO2004108071A2 (en) 2003-06-05 2004-12-16 Salk Institute For Biological Studies Targeting polypeptides to the central nervous system
US20050026823A1 (en) 2003-06-20 2005-02-03 Biomarin Pharmaceutical Inc. Use of the chaperone receptor-associated protein (RAP) for the delivery of therapeutic compounds to the brain and other tissues
JP5624256B2 (ja) 2003-06-20 2014-11-12 ラプター・ファーマシューティカル・インコーポレイテッド 脳および他の組織への治療化合物の送達
CA2534899A1 (en) 2003-08-08 2005-02-17 Tissue Targeting Japan Inc. Polypeptides having brain-localizing activity and uses thereof
EP1663278A4 (de) 2003-08-28 2009-07-29 Biorexis Pharmaceutical Corp Epo mimetika-peptide und fusionsproteine
US20050058702A1 (en) 2003-09-17 2005-03-17 Ben-Sasson Shmuel A. Compositions capable of facilitating penetration across a biological barrier
US20050208095A1 (en) 2003-11-20 2005-09-22 Angiotech International Ag Polymer compositions and methods for their use
US7208174B2 (en) 2003-12-18 2007-04-24 Hoffmann-La Roche Inc. Liposome compositions
AU2005265164A1 (en) * 2004-06-17 2006-01-26 Musc Foundation For Research Development Non-natural amino acids
CA2569381A1 (en) 2004-07-21 2006-08-31 Ambrx, Inc. Biosynthetic polypeptides utilizing non-naturally encoded amino acids
NZ553224A (en) 2004-07-26 2009-05-31 Asterion Ltd Linkers
CA2580189C (en) 2004-09-29 2013-05-21 Children's Memorial Hospital Sirna-mediated gene silencing of alpha synuclein
US9002652B1 (en) 2005-01-27 2015-04-07 Institute For Systems Biology Methods for identifying and using organ-specific proteins in blood
EP3248600B8 (de) 2005-02-18 2020-06-24 Abraxis BioScience, LLC Kombinationen und modi zur verabreichung therapeutischer mittel und kombinationstherapie
US20090016959A1 (en) 2005-02-18 2009-01-15 Richard Beliveau Delivery of antibodies to the central nervous system
JP5137814B2 (ja) 2005-04-06 2013-02-06 ジェンザイム・コーポレーション 治療ターゲティングのための酸不安定リンカーを介するｐｅｇおよびポリシアルリソソーム酵素のコンジュゲート
KR20080030564A (ko) 2005-05-12 2008-04-04 태피스트리 파마슈티컬스 인코퍼레이티드 표적 컨쥬게이트에 적합한 분자 구조물
WO2006138343A2 (en) 2005-06-14 2006-12-28 Raptor Pharmaceutical Inc. Compositions comprising receptor - associated protein (rap) variants specific for lrp2 and uses thereof
EP1907009A4 (de) 2005-07-15 2009-09-02 Angiochem Inc Verwendung von aprotinin-polypeptiden als träger in pharmazeutischen konjugaten
EP1904642A4 (de) 2005-07-19 2008-11-26 Univ Illinois Transportmittel zur überquerung der blut-hirn-schranke und zum eindringen in gehirnkrebszellen sowie verwendungsverfahren dafür
GB0517092D0 (en) 2005-08-19 2005-09-28 Novartis Ag New compositions containing taxane derivatives
AU2006287481A1 (en) 2005-09-08 2007-03-15 Mdrna, Inc. Pharmaceutical compositions for delivery of ribonucleic acid to a cell
EP1945240B1 (de) 2005-09-16 2016-12-28 Raptor Pharmaceutical Inc Zusammensetzungen mit rezeptor-assoziierten protein (rap) varianten, die für cr-haltige proteine spezifisch sind und ihre verwendungen
US8053569B2 (en) 2005-10-07 2011-11-08 Armagen Technologies, Inc. Nucleic acids encoding and methods of producing fusion proteins
EP1951737A4 (de) 2005-11-01 2009-07-01 Alnylam Pharmaceuticals Inc Rnai-hemmung von influenza-virus-neubildungen
US8039432B2 (en) 2005-11-09 2011-10-18 Conjuchem, Llc Method of treatment of diabetes and/or obesity with reduced nausea side effect
US20100130432A1 (en) * 2005-12-16 2010-05-27 Argolyn Bioscience Inc. and Medical University of South Carolina [MUSC] Non-Natural Amino Acids and Neurotensin Analogues Thereof
US8290433B2 (en) 2007-11-14 2012-10-16 Blaze Mobile, Inc. Method and system for securing transactions made through a mobile communication device
AR054215A1 (es) 2006-01-20 2007-06-13 Eriochem Sa Una formulacion farmaceutica de un taxano, una composicion solida de un taxano liofilizado a partir de una solucion de acido acetico, un procedimiento para la preparacion de dicha composicion solida de un taxano, una composicion solubilizante de un taxano liofilizado, y un conjunto de elementos (kit
AU2007223888A1 (en) 2006-03-06 2007-09-13 Amunix, Inc. Genetic packages and uses thereof
US7477504B1 (en) 2006-03-13 2009-01-13 C.P.D. Technologies, Inc. Versatile stun glove
ATE451392T1 (de) 2006-03-30 2009-12-15 Glaxo Group Ltd Gegen amyloid-beta peptid gerichtete antikörper
EP2043696B1 (de) 2006-07-13 2015-02-25 Burnham Institute for Medical Research Verfahren und zusammensetzungen zum gc1qr/p32-targeting
CA2658654A1 (en) 2006-07-24 2008-01-31 Biorexis Pharmaceutical Corporation Exendin fusion proteins
WO2008036682A2 (en) 2006-09-18 2008-03-27 Raptor Pharmaceutical Inc. Treatment of liver disorders by administration of receptor-associated protein (rap)-conjugates
CA2666841A1 (en) 2006-10-19 2008-04-24 Angiochem, Inc. Compounds for stimulating p-glycoprotein function and uses thereof
US20100184692A1 (en) 2006-10-27 2010-07-22 University Of Kentucky Research Foundation Amidated Dopamine Neuron Stimulating Peptides for CNS Dopaminergic Upregulation
US9399675B2 (en) 2007-02-28 2016-07-26 The Board Of Regents Of The University Of Oklahoma Methods and compositions for diagnosing Alzheimer's disease and age-related macular degeneration
EP2132224B1 (de) 2007-03-21 2011-12-28 Raptor Pharmaceutical Inc Cyclische rezeptor-assoziierte-proteine (rap)-peptide
US20090062212A1 (en) 2007-05-07 2009-03-05 Elliott Richelson Peptide analogs that are potent and selective for human neurotensin preceptor subtype 2
US9365634B2 (en) 2007-05-29 2016-06-14 Angiochem Inc. Aprotinin-like polypeptides for delivering agents conjugated thereto to tissues
AU2008255556B2 (en) 2007-05-29 2014-08-07 Angiochem, Inc. Aprotinin-like polypeptides for delivering agents conjugated thereto to tissues
US8802631B2 (en) 2007-09-17 2014-08-12 Ludwig Institute For Cancer Research Ltd. Peptides and methods for the treatment of gliomas and other cancers
CN101939027B (zh) 2007-10-02 2014-07-30 玛瑞纳生物技术有限公司 用于递送核酸的脂肽
WO2009070597A2 (en) 2007-11-26 2009-06-04 Armagen Technologies, Inc. Fusion proteins for delivery of gdnf to the cns
AU2008340943A1 (en) 2007-12-20 2009-07-02 Angiochem Inc. Polypeptide-nucleic acid conjugates and uses thereof
US8193182B2 (en) 2008-01-04 2012-06-05 Intellikine, Inc. Substituted isoquinolin-1(2H)-ones, and methods of use thereof
ES2951646T3 (es) 2008-02-21 2023-10-24 Burnham Institute For Medical Res Métodos y composiciones relacionados con péptidos y proteínas con elementos C-terminales
DK2279008T3 (en) 2008-04-18 2019-04-29 Angiochem Inc PHARMACEUTICAL COMPOSITIONS OF PACLITAXEL, PACLITAXEL ANALOGS OR PACLITAXEL CONJUGATES AND RELATED PROCEDURES FOR PREPARATION AND USE
US20110117627A1 (en) 2008-07-10 2011-05-19 The Board Of Trustees Of The University Of Illinois Regulation of apoptosis by neural specific splice variants of ig20
RU2531591C2 (ru) 2008-10-15 2014-10-20 Ангиокем Инк. Конъюгаты этопозида и доксорубицина для доставки лекарственных средств
CN102245642A (zh) 2008-10-15 2011-11-16 安吉奥开米公司 Glp-1激动剂的结合物及其用途
JP2012510798A (ja) 2008-12-05 2012-05-17 アンジオケム インコーポレーテッド ペプチド治療剤コンジュゲートおよびその使用
AU2009322043A1 (en) 2008-12-05 2011-07-07 Angiochem Inc. Conjugates of neurotensin or neurotensin analogs and uses thereof
MX2011005965A (es) 2008-12-05 2011-09-01 Angiochem Inc Conjugados de leptina y de análogos de leptina y sus usos de los mismos.
BRPI0922611A2 (pt) 2008-12-17 2018-11-06 Angiochem Inc inibidores de metaloproteína de matriz de membrana tipo 1 e usos dos mesmos
US20110318322A1 (en) 2009-01-12 2011-12-29 Nektar Therapeutics Conjugates of a Lysosomal Enzyme Moiety and a Water Soluble Polymer
CA2759129C (en) 2009-04-20 2018-12-11 Angiochem Inc. Treatment of ovarian cancer using an anticancer agent conjugated to an angiopep-2 analog
US20100284921A1 (en) 2009-05-08 2010-11-11 Temple University - Of The Commonwealth System Of Higher Education Targeted nanoparticles for intracellular cancer therapy
CN102753187A (zh) 2009-06-03 2012-10-24 戴瑟纳制药公司 肽-dicer底物试剂及其特异性抑制基因表达的方法
MX2011013258A (es) 2009-06-11 2012-02-28 Angiochem Inc Proteinas de fusion para entrega de gdnf y bdnf al sistema nervioso central.
US9161988B2 (en) 2009-07-02 2015-10-20 Angiochem Inc. Multimeric peptide conjugates and uses thereof
EP3000481A3 (de) 2009-07-14 2016-05-11 Mayo Foundation for Medical Education and Research Peptidvermittelte nicht-kovalente verabreichung von wirkstoffen über die blut-hirn-schranke
CN102781965A (zh) 2009-10-06 2012-11-14 安吉奥开米公司 用于转运治疗剂的组合物和方法
US8530429B2 (en) 2009-11-24 2013-09-10 Arch Cancer Therapeutics, Inc. Brain tumor targeting peptides and methods
US9095541B2 (en) 2009-11-24 2015-08-04 Arch Cancer Therapeutics, Inc. Brain tumor targeting peptides and methods
EP2333074A1 (de) 2009-12-14 2011-06-15 Robert Steinfeld Substanzen und Verfahren zur Behandlung von lyosomalen Speicherkrankheiten
DK2544674T3 (da) 2010-03-08 2018-01-29 Sloan Kettering Inst Cancer Res Cdc7-kinaseinhibitorer og anvendelser deraf
WO2011119549A1 (en) 2010-03-22 2011-09-29 President And Fellows Of Harvard College Trioxacarcins and uses thereof
WO2011119608A1 (en) 2010-03-26 2011-09-29 University Of Tennessee Research Foundation Peptides that specifically target amyloid deposits
WO2011127580A1 (en) 2010-04-14 2011-10-20 National Research Council Of Canada Compositions and methods for brain delivery of analgesic peptides
WO2011153642A1 (en) 2010-06-10 2011-12-15 Angiochem Inc. Leptin and leptin analog conjugates and fusion proteins and uses thereof
CN103080125A (zh) 2010-07-02 2013-05-01 安吉奥开米公司 用于治疗性结合物的短且含d氨基酸的多肽及其使用
US8218280B2 (en) 2010-07-08 2012-07-10 Schneider Electric USA, Inc. Secondary thermal sensor for primary conductors
WO2012018404A2 (en) 2010-08-06 2012-02-09 U3 Pharma Gmbh Use of her3 binding agents in prostate treatment
CN102406949B (zh) 2010-09-21 2013-05-29 复旦大学 一种靶向示踪的多模式诊断纳米影像药物
WO2012037687A1 (en) 2010-09-23 2012-03-29 Angiochem Inc. Therapeutic polypeptides and uses thereof
CA2817577A1 (en) 2010-11-10 2012-05-18 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
WO2012068531A2 (en) 2010-11-18 2012-05-24 The General Hospital Corporation Novel compositions and uses of anti-hypertension agents for cancer therapy
CN102552928A (zh) 2010-12-19 2012-07-11 复旦大学 一种治疗脑部肿瘤的双级靶向递药系统及其制备方法
UA115767C2 (uk) 2011-01-10 2017-12-26 Інфініті Фармасьютікалз, Інк. Способи отримання ізохінолінонів і тверді форми ізохінолінонів
CN102614105A (zh) 2011-01-28 2012-08-01 复旦大学 一种脑靶向载两性霉素b聚合物胶束给药系统
EP2680820B1 (de) 2011-03-01 2022-11-02 2-BBB Medicines B.V. Fortschrittliches, aktives liposomales laden von schwer wasserlöslichen substanzen
PL2691443T3 (pl) 2011-03-28 2021-08-30 Massachusetts Institute Of Technology Sprzężone lipomery i ich zastosowania
EP2952210A3 (de) 2011-04-07 2016-03-16 Emory University Zusammensetzungen mit saccharidbindenden teilen und verfahren zur gezielten therapie
JP2014518862A (ja) 2011-05-09 2014-08-07 インスティトゥト・キミク・デ・サリア 薬物送達用ポリマーナノ粒子
WO2013004716A1 (en) 2011-07-04 2013-01-10 Universität Basel Peptide beads
US8969363B2 (en) 2011-07-19 2015-03-03 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9056877B2 (en) 2011-07-19 2015-06-16 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
CA2844742A1 (en) 2011-08-11 2013-02-14 Intellikine, Llc Kinase inhibitor polymorphs
PE20141371A1 (es) 2011-08-29 2014-10-13 Infinity Pharmaceuticals Inc Compuestos heterociclicos y usos de los mismos
WO2013049332A1 (en) 2011-09-29 2013-04-04 Infinity Pharmaceuticals, Inc. Inhibitors of monoacylglycerol lipase and methods of their use
WO2013056096A1 (en) 2011-10-13 2013-04-18 Angiochem Inc. Polypeptide-opioid conjugates and uses thereof
CN107522664B (zh) 2011-10-27 2021-03-16 麻省理工学院 能够形成药物包封微球的在n末端上官能化的氨基酸衍生物
US9403820B2 (en) 2011-11-11 2016-08-02 Intellikine Llc Kinase inhibitor polymorphs
US20150037311A1 (en) 2011-12-01 2015-02-05 Angiochem Inc. Targeted lysosomal enzyme compounds
HUE052136T2 (hu) 2011-12-13 2021-04-28 Engeneic Molecular Delivery Pty Ltd Bakteriális eredetû intakt minisejtek terápiás szerek agydaganatokba történõ bejuttatására
CA2859205A1 (en) 2011-12-16 2013-06-20 Massachusetts Institute Of Technology Alpha-aminoamidine polymers and uses thereof
WO2013120107A1 (en) 2012-02-09 2013-08-15 University Of Rochester Methods and compositions for treating a subject to inhibit hearing loss
EP3153523A3 (de) 2012-03-02 2017-05-03 Icahn School of Medicine at Mount Sinai Varianten von prothymosin alpha und verfahren zur verwendung davon
CN108686203A (zh) 2012-04-04 2018-10-23 哈洛齐梅公司 使用抗透明质酸剂和肿瘤靶向紫杉烷的组合疗法
EP4005600A1 (de) 2012-04-26 2022-06-01 Yale University Gegen hiv gerichtete zytotoxische wirkstoffe freisetzende moleküle (cdm-hs), zytotoxische wirkung gegen das menschliche immunschwächevirus und verfahren zur verwendung
CN104662151A (zh) 2012-06-15 2015-05-27 安吉奥开米公司 靶向的艾杜糖醛酸酶化合物
WO2014026286A1 (en) 2012-08-14 2014-02-20 Angiochem Inc. Conjugates including an antibody moiety, a polypeptide that traverses the blood-brain barrier, and a cytotoxin
EP2885318A4 (de) 2012-08-14 2016-03-30 Angiochem Inc Peptid-dendrimer-konjugate und ihre verwendungen
AU2013344253A1 (en) 2012-11-12 2015-05-28 Angiochem Inc. Aprotinin-derived polypeptide-antibody conjugates
JP2015536658A (ja) 2012-11-30 2015-12-24 アンジオケム インコーポレーテッド 標的化イズロン酸−２−スルファターゼ化合物
WO2014194428A1 (en) 2013-06-06 2014-12-11 Angiochem Inc. Targeted heparan sulfatase compounds
US20160367691A1 (en) 2013-06-06 2016-12-22 Angiochem Inc. Targeted enzyme compounds and uses thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040162284A1 (en) * 2003-02-19 2004-08-19 Harris Herbert W. Method of lowering body temperature with (S) tofisopam
WO2006086870A1 (en) * 2005-02-18 2006-08-24 Angiochem Inc. Aprotinin polypeptides for transporting a compound across the blood-brain barrier

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
BOULES M ET AL: "Bioactive analogs of neurotensin: Focus on CNS effects", PEPTIDES, vol. 27, no. 10, 1 October 2006 (2006-10-01), pages 2523-2533, XP027957628, ISSN: 0196-9781 [retrieved on 2006-10-01] *
BUVANENDRAN ET AL: "Recent advances in nonopioid analgesics for acute pain management", TECHNIQUES IN REGIONAL ANESTHESIA AND PAIN MANAGEMENT, vol. 11, no. 1, 30 April 2007 (2007-04-30) , pages 19-26, XP022056392, ISSN: 1084-208X, DOI: 10.1053/J.TRAP.2007.02.002 *
KATSUHIKO YANO ET AL: "Simultaneous activation of two different receptor systems by enkephalin/neurotensin conjugates having spacer chains of various lengths", EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 7, no. 1, 1 December 1998 (1998-12-01), pages 41-48, XP055047408, ISSN: 0928-0987, DOI: 10.1016/S0928-0987(98)00002-5 *
See also references of WO2010063122A1 *
WILLIAMSON P ET AL: "Expression and Purification of Recombinant Neurotensin in Escherichia coli", PROTEIN EXPRESSION AND PURIFICATION, vol. 19, no. 2, 1 July 2000 (2000-07-01), pages 271-275, XP027414850, ISSN: 1046-5928, DOI: 10.1006/PREP.2000.1246 [retrieved on 2000-07-01] *

Also Published As

Publication number Publication date
EP2370471A4 (de) 2013-05-01
JP2015178527A (ja) 2015-10-08
US9914754B2 (en) 2018-03-13
WO2010063122A1 (en) 2010-06-10
ZA201104495B (en) 2012-08-29
JP5759379B2 (ja) 2015-08-05
US20100256055A1 (en) 2010-10-07
AU2009322043A1 (en) 2011-07-07
CA2745524C (en) 2020-06-09
MX2011005963A (es) 2011-09-01
CA2745524A1 (en) 2010-06-10
BRPI0922689A2 (pt) 2018-11-06
EP2370471B1 (de) 2017-02-22
CN102307904A (zh) 2012-01-04
JP2012510796A (ja) 2012-05-17

Similar Documents

Publication Publication Date Title
US9914754B2 (en) Conjugates of neurotensin or neurotensin analogs and uses thereof
US8921314B2 (en) Conjugates of GLP-1 agonists and uses thereof
US20110288009A1 (en) Leptin and leptin analog conjugates and uses thereof
US20120196803A1 (en) Fusion proteins for delivery of gdnf and bdnf to the central nervous system
US20140335163A1 (en) Targeted iduronate-2-sulfatase compounds
WO2011153642A1 (en) Leptin and leptin analog conjugates and fusion proteins and uses thereof
US20150147310A1 (en) Targeted enzyme compounds and uses thereof
EP2794663A1 (de) Therapeutische peptidkonjugate und ihre verwendung
AU2012344702A1 (en) Targeted lysosomal enzyme compounds
WO2014194428A1 (en) Targeted heparan sulfatase compounds

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20110630

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK SM TR

RIN1 Information on inventor provided before grant (corrected)

Inventor name: THIOT, CARINE

Inventor name: CHE, CHRISTIAN

Inventor name: DEMEULE, MICHEL

Inventor name: CASTAIGNE, JEAN-PAUL

Inventor name: GAGNON, CATHERINE

DAX Request for extension of the european patent (deleted)
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1162541

Country of ref document: HK

A4 Supplementary search report drawn up and despatched

Effective date: 20130404

RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 47/48 20060101ALI20130327BHEP

Ipc: C07K 14/81 20060101ALI20130327BHEP

Ipc: C07K 19/00 20060101AFI20130327BHEP

Ipc: C12N 15/62 20060101ALI20130327BHEP

Ipc: C07K 17/00 20060101ALI20130327BHEP

Ipc: A61K 38/16 20060101ALI20130327BHEP

Ipc: C07K 7/08 20060101ALI20130327BHEP

17Q First examination report despatched

Effective date: 20150325

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 38/16 20060101ALI20160511BHEP

Ipc: A61K 47/48 20060101ALI20160511BHEP

Ipc: C07K 7/08 20060101ALI20160511BHEP

Ipc: C07K 19/00 20060101AFI20160511BHEP

INTG Intention to grant announced

Effective date: 20160616

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK SM TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 38/16 20060101ALI20170117BHEP

Ipc: C07K 19/00 20060101AFI20170117BHEP

Ipc: C07K 7/08 20060101ALI20170117BHEP

Ipc: A61K 47/50 20170101ALI20170117BHEP

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 869192

Country of ref document: AT

Kind code of ref document: T

Effective date: 20170315

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602009044384

Country of ref document: DE

REG Reference to a national code

Ref country code: CH

Ref legal event code: NV

Representative=s name: RENTSCH PARTNER AG, CH

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG4D

REG Reference to a national code

Ref country code: NL

Ref legal event code: MP

Effective date: 20170222

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK05

Ref document number: 869192

Country of ref document: AT

Kind code of ref document: T

Effective date: 20170222

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170222

Ref country code: NO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170522

Ref country code: HR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170222

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170523

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170222

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170222

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170222

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170222

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170222

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170522

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170622

Ref country code: ES

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170222

REG Reference to a national code

Ref country code: CH

Ref legal event code: PCAR

Free format text: NEW ADDRESS: BELLERIVESTRASSE 203 POSTFACH, 8034 ZUERICH (CH)

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170222

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170222

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170222

Ref country code: IT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170222

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170222

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602009044384

Country of ref document: DE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SM

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170222

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170222

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170222

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 9

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

REG Reference to a national code

Ref country code: HK

Ref legal event code: GR

Ref document number: 1162541

Country of ref document: HK

26N No opposition filed

Effective date: 20171123

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170222

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171207

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171207

REG Reference to a national code

Ref country code: BE

Ref legal event code: MM

Effective date: 20171231

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171207

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171231

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170222

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO

Effective date: 20091207

REG Reference to a national code

Ref country code: DE

Ref legal event code: R082

Ref document number: 602009044384

Country of ref document: DE

Representative=s name: PATENTANWAELTE ISENBRUCK BOESL HOERSCHLER PART, DE

Ref country code: DE

Ref legal event code: R081

Ref document number: 602009044384

Country of ref document: DE

Owner name: ANGIOCHEM INC., WESTMOUNT, CA

Free format text: FORMER OWNER: ANGIOCHEM INC., MONTREAL, QUEBEC, CA

REG Reference to a national code

Ref country code: CH

Ref legal event code: PCOW

Free format text: NEW ADDRESS: 4150 RUE SAINTE-CATHERINE OUEST SUITE 490, WESTMOUNT QC H3Z 2Y5 (CA)

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CY

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170222

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170222

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170222

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170622

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20211227

Year of fee payment: 13

Ref country code: GB

Payment date: 20211227

Year of fee payment: 13

Ref country code: DE

Payment date: 20211227

Year of fee payment: 13

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 20220104

Year of fee payment: 13

REG Reference to a national code

Ref country code: DE

Ref legal event code: R082

Ref document number: 602009044384

Country of ref document: DE

Representative=s name: SIMMONS & SIMMONS LLP, DE

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 602009044384

Country of ref document: DE

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20221207

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20221231

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20221207

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230701

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20221231

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20221231